Submissions for variant NM_007294.4(BRCA1):c.5090G>A (p.Cys1697Tyr)

dbSNP: rs397507241

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen	RCV004566763	SCV004101450	likely pathogenic	BRCA1-related cancer predisposition	2024-06-11	reviewed by expert panel	curation	The c.5090G>A variant in BRCA1 is a missense variant predicted to cause substitution of Cysteine by Tyrosine at amino acid 1697 (p.Cys1697Tyr). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth >=25) and gnomAD v3.1 (non-cancer subset, read depth >=25) (PM2_Supporting met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.386, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. SpliceAI predictor score of 0.02 suggests that the variant has no impact on splicing (score threshold <0.10) (PP3 met). Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 30209399, PMID: 30765603) (PS3 met). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3, PS3).
Ambry Genetics	RCV000129997	SCV000184821	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-03-22	criteria provided, single submitter	clinical testing	The p.C1697Y variant (also known as c.5090G>A), located in coding exon 16 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5090. The cysteine at codon 1697 is replaced by tyrosine, an amino acid with highly dissimilar properties. Both this alteration, as well as a close-match at the same codon (p.C1697R), have been reported in multiple HBOC families (Bergthorsson JT et al. J. Med. Genet. 2001 Jun;38:361-8; Biunno I et al. Fam. Cancer. 2014 Sep;13:437-44). In addition, both alterations have demonstrated abnormal protein function with respect to transactivation, protein/peptide binding, protein stability/steady-state levels, and homology-directed repair (Woods NT et al. npg Genomic Medicine. 2016: 1:16001; Vallon-Christersson J et al. Hum. Mol. Genet. 2001 Feb;10:353-60; Glover JN. Fam. Cancer. 2006;5:89-93; Williams RS et al. J. Biol. Chem. 2003 Dec;278:53007-16; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Ambry internal data). One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 10;562:217-222). Internal structural analysis indicates that both amino acid substitutions are predicted to disrupt the protein-protein binding interface of BRCA1 (Clapperton JA et al. Nat. Struct. Mol. Biol. 2004 Jun;11:512-8; Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature. 2016 08;536:285-91). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000464859	SCV000549322	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1697 of the BRCA1 protein (p.Cys1697Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 24729269, 29470806). ClinVar contains an entry for this variant (Variation ID: 37635). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 28781887, 30209399). This variant disrupts the p.Cys1697 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11157798, 11389159, 18465347). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000501879	SCV000916752	uncertain significance	not specified	2018-06-05	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5090G>A (p.Cys1697Tyr) results in a non-conservative amino acid change located in the BRCT domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246440 control chromosomes. c.5090G>A has been reported in the literature in an individual affected with Hereditary Breast and Ovarian Cancer. However, this report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence evaluating transcriptional activity, which indicated that the variant abolishes normal transcription (Woods_2016). However, this assay was performed using a partial BRCA1 protein in HEK293 cells, rather than the tissue of interest, which may not accurately reflect clinical significance. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
GeneDx	RCV003318545	SCV004022995	pathogenic	not provided	2023-01-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5209G>A; This variant is associated with the following publications: (PMID: 18465347, 24729269, 11389159, 15133502, 21447777, 28781887, 17305420, 20516115, 32377563, 32257056, 29884841, 25348405, 24389207, 11157798, 35665744, 30209399, 16528612, 14534301, 30263132, 30765603, 30982232, 29470806)
Sharing Clinical Reports Project (SCRP)	RCV000031216	SCV000053816	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2011-12-09	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353519	SCV000591578	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Cys1697Tyr variant was not identified in the literature nor was it identified in the Exome Variant Server, HGMD, UMD, COSMIC, LOVD or BIC databases. The p.Cys1697 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) suggest that the p.Cys1697Tyr variant may impact the protein. In addition, Domchek (2013) notes that this residue is required for BRCA1 carboxyl-terminal (BRCT) domain function in DNA repair and tumor suppression. However, this information is not predictive enough to assume pathogenicity. A different variant at this amino acid position, p.Cys1697Arg (c.5089T>C) has been reported in the literature and in the HGMD, UMD, BIC and LOVD databases. Five functional studies have demonstrated that the p.Cys1697Arg variant has an impact on protein structure or expression (Bergthorsson 2001, Lee 2010, Vallon-Christersson 2001, Williams 2003, Williams 2004) and one study showed segregation of this variant with disease in one family (Vallon-Christersson 2001), which suggests that this residue is important to BRCA1 function. However, it should be noted that these results are limited to the substitution of an amino acid (p.Cys1697Arg) that differs from the variant that was found (p.Cys1697Tyr). In summary, based on the above information, the clinical significance of this variant cannot be determined at this time. Therefore, this variant is classified as a variant of unknown significance.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735461	SCV000863598	uncertain significance	Breast and/or ovarian cancer	2013-03-15	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000031216	SCV001242099	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro