Table 1 Comparison of biallelic BRCA1 variant carriers regarding their genotype, phenotype, rescue mechanisms and classification of the detected variants¹

Seo et al. [1]

c.1115G > A, p.(Trp372*)

c.1115G > A, p.(Trp372*)

Sibs

♀, FA, T-ALL (5y),

♀, FA, NC (8y)

Sib 1—DEB sensitive and spontaneous;

Sib 2—elevated chromosomal sensitivity to DEB and MMC

∆11q

∆11q

C5

C5

Variant alleles predicted to encode a truncated non-functional protein

Seo et al. [1]

c.1292 T > G, p.(Leu431*)

c.1292 T > G, (p.Leu431*)

Sibs:

♀, FA, NB (2y),

♂, FA, NC (15.5y)

Both sibs, DEB sensitive and spontaneous

∆11q

∆11q

C5

C5

Variant alleles predicted to encode a truncated non-functional protein

Sawyer et al. [4]

c.594_597del, p.(Ser198Argfs*35)

c.5095C > T, p.(Arg1699Trp)

♀, FA, BC (23y)

DEB and MMC sensitive

∆9–10, and ▼10p (r.594-21_594-1ins)

missense

n.a

C5

c.594_597del results in a truncation in BRCA1 exon 10 (de la Hoya et al. [29]), where ∆9–10 is shown to be naturally occurring isoform

c.5095C > T: IARC C5 based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. [30]. Posterior probability = 1 (Lindor et al. [31])

Domchek et al. [2]

c.2457delC, p.(Asp825Glufs*21)

c.5207 T > C, p.(Val1736Ala)

♀, FA, OC (28y)

Not tested

∆11q

missense

C5

C5

c.2457delC allele predicted to encode a truncated non-functional protein

c.5207T > C: IARC C5 based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. [30]. Posterior probability = 0.9998

Freire et al. [7]

c.2709 T > A, p.(Cys903*)

c.2709 T > A, p.(Cys903*)

♀, FA, NC (3.7y)

DEB sensitive and spontaneous

∆11q

∆11q

n.a

n.a

Variant alleles predicted to encode a truncated non-functional protein

Keupp et al. [3]

c.181 T > G, p.(Cys61Gly)

c.5096G > A, p.(Arg1699Gln)

♀, mild FA, BC (30y)

DEB‐induced chromosome fragility in patient-derived blood lymphocytes within normal range

p.(Cys61Gly)

moderate penetrance missense

C5

C5

c.181T > G IARC C5 based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. [30]. Posterior probability = 1 (Lindor et al. [31])

The c.5096G > A variant has been shown to impact function [22, 32,33,34,35]. A genetic study ([16]) reported it to be associated with reduced risk compared to another pathogenic missense substitution variant at the same residue (BRCA1 c.5095C > T p.(Arg1699Trp)). A subsequent larger genetic study including 129 families ([17]) reported HRs of 2.83 for breast cancer and 5.83 for ovarian cancer risk, and estimated the cumulative risk to age 70 to be 20% for breast cancer and 6% for ovarian cancer. This variant is considered pathogenic with reduced penetrance relative to the average BRCA1 truncating pathogenic variant

Chirita-Emandi et al. [8]

c.2933dupA, p.(Tyr978*)

c.843_846delCTCA, p.(Ser282TyrfsTer15)

♂ FA, NC (2y)

DEB and MMC sensitive

∆11q

∆11q

n.a

C5

Variant alleles predicted to encode a truncated non-functional protein

Kwong et al. [36]

c.4065_4068delTCAA, p.(Asn1355Lysfs*10)

c.5406 + 7A > G, p.?

♀, no or very subtle FA features, OC (43y), BC (44y)

No definitive diagnostic test for FA was performed due to a lack of clinical indication of FA-like features being observed

∆11q

Partial effect on splicing (not quantified)

C5

n.a. (likely benign in ClinVar

c.4065_4068delTCAA predicted to encode a truncated non-functional protein (ENIGMA Rules, Version 2.5.1, 29 June 2017)

For c.5406 + 7A > G, the authors analyzed cDNA from blood and identified cryptic splicing with deletion of 74 nucleotides from transcript and predicted frameshift. However, the RNA result was not quantitated. No other quantitative studies of the variant are available

Borlin et al. [37]

c.1116G > A, p.(Trp372*)

c.5017_5019del, p.(His1673del)

♀, FA, CNS (1y)

MMC-induced chromosomal breakage analysis in peripheral blood lymphocytes showed strongly reduced proliferation upon stimulation, but no evidence of increased chromosomal breakage

∆11q

In-frame deletion

C5

Clinvar C3, C4

c.1116G > A allele predicted to encode a truncated non-functional protein

c.5017_5019del considered pathogenic by 8/13 submitters in Clinvar

This study

c.2475delC, p.(Asp825Glufs*21)

Ex20dup

♀, no FA symptoms, LC (64y)

MMC within normal range, Lymphoblastic cell line

∆11q

no exon 20 skipping

C5

C3

c.2457delC allele predicted to encode a truncated non-functional protein

Ex20dup function similar to p.(Arg1699Gln) indicating possibly moderate penetrance. See discussion for ACMG classification