ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4964C>T (p.Ser1655Phe) (rs80357390)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000223580 SCV000277296 likely pathogenic Hereditary cancer-predisposing syndrome 2020-08-18 criteria provided, single submitter clinical testing The p.S1655F variant (also known as c.4964C>T), located in coding exon 14 of the BRCA1 gene, results from a C to T substitution at nucleotide position 4964. The serine at codon 1655 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple individuals with personal and/or family history consistent with Hereditary Breast and Ovarian Cancer syndrome (HBOC) (Gómez García et al. Breast Cancer Res. 2009; 11(1):1-12; Mohammadi et al. BMC Cancer. 2009; 9:211; Arai M et al. J. Hum. Genet. 2018 Apr;63:447-457; Cotrim DP et al. BMC Cancer. 2019 Jan;19:4). Results from two different functional studies showed this variant results in abrogation of transcriptional activation function of the protein (Carvalho et al. Cancer Res. 2007; 67(4):1494-501; Lee MS et al. Cancer Res. 2010; 70(12):4880-90; Bouwman P et al. Cancer Discov. 2013; 3(10):1142-55). An additional 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). Experimental results from three independent studies showed that the p.S1655 residue is part of the hydrophobic phosphopeptide binding pocket of the BRCA1 protein which mediates interactions of the BRCA1 protein with various phosphopeptides in order to perform the transactivation function of the protein (Williams RS et al. Nat Struct Mol Biol. 2004; 11(6):519-25; Shiozaki et al. Mol Cell. 2004; 4(3):405-12; Lee MS et al. Cancer Res. 2010; 70(12):4880-90). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this variant is predicted to be highly destabilizing to the local structure (Ambry internal data). 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.
Mendelics RCV000709466 SCV000839224 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV000709466 SCV000897862 pathogenic Hereditary breast and ovarian cancer syndrome 2018-10-31 criteria provided, single submitter clinical testing Data included in classification: The variant was observed in 2 independent UK families undergoing clinical diagnostic testing, the denominator of which dataset of clinical testing was 16,600. Case control comparison against ethnically matched population data (2/16,600 in familial cases against 0/63,369 GNOMAD NFE controls pexact= 0.04 (PS4). The variant is absent in the remainder of the GNOMAD populations (75,263 individuals) (PM2). Predicted deleterious on SIFT, Align GVGD and Polyphen HumVar (PP3). Non-functional in SGE haploid BRCA1-assay (Findlay et al. 2018), an assay well validated against ENIGMA/ClinVar (PS3) The variant is located in the BRCT1 domain (PM1_sup). c.4963T>C p.(Ser1655Pro) previously classified as pathogenic by CanVIG (July 2018) (PM5). Data not included in classification: Extensive additional functional data demonstrating variant to be deleterious: Williams et al. Carvalho et al. Lee et al., Bouwman et al (2013), Domchek et al (2013), Shakya (2011). Anantha et al (2017) elife; 6 e21350 Apr: undertook functional studies confirming reduced HR activity. Computer based algorithms predicting variant to be deleterious: Iverson (2012), Gomez-Garcia (2009) and Karchin (2007). Segregation 1 in 4 in UK family. Gomez-Garcia et al (2009) demonstrated segregation in 6/6 individuals (across 2 families) but no further details provided. There are additional reports of this variant in ClinVar (2), BIC (3) and BRCA1 LOVD (11).
Mendelics RCV000112436 SCV001140497 likely pathogenic Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000709466 SCV001478730 pathogenic Hereditary breast and ovarian cancer syndrome 2021-01-21 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4964C>T (p.Ser1655Phe) results in a non-conservative amino acid change in 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 250710 control chromosomes. c.4964C>T has been widely reported in the literature and subsequently cited by others to co-segregate with disease in multiple individuals from families affected with Hereditary Breast And Ovarian Cancer (example, Gomez_Garcia_2009), as an isolated occurrence in a proband reporting a positive history of breast cancer (example, Cotrim_2019), and isolated reports in individuals with breast cancer (example, Inagaki-Kawata_2020). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function (example, Bouwman_2020, Findlay_2018). The most pronounced variant effect results in defective homologous recombination DNA repair activity in independent measures of evaluation. Multiple clinical diagnostic laboratories and one cancer variant interpretation group have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=1)/likely pathogenic (n=3). Some cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000709466 SCV001579488 pathogenic Hereditary breast and ovarian cancer syndrome 2020-03-23 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 1655 of the BRCA1 protein (p.Ser1655Phe). The serine residue is highly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with breast and/or ovarian cancer, and was observed to segregate with disease in several families (PMID: 19200354, 19563646, 24249303, 27767231, 29176636). ClinVar contains an entry for this variant (Variation ID: 55333). This variant has been reported to affect BRCA1 protein function (PMID: 15133502, 15133503, 17308087, 23867111, 20516115, 28398198). For these reasons, this variant has been classified as Pathogenic.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112436 SCV000145224 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000112436 SCV001243277 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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