ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5282T>C (p.Phe1761Ser)

dbSNP: rs80356905
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131349 SCV000186324 likely pathogenic Hereditary cancer-predisposing syndrome 2018-06-21 criteria provided, single submitter clinical testing The p.F1761S variant (also known as c.5282T>C), located in coding exon 19 of the BRCA1 gene, results from a T to C substitution at nucleotide position 5282. The phenylalanine at codon 1761 is replaced by serine, an amino acid with highly dissimilar properties. This alteration was detected in one individual from a cohort of 135 Japanese patients suspected of having HBOC (Sugano K et al. Cancer Sci. 2008 Oct;99:1967-76). This alteration was also severely compromised in multiple functional assays including in binding activity, transcription activation and binding specificity (Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Hayes F et al. Cancer Res. 2000 May;60:2411-8). Internal structural analysis identified this alteration as being within a mutational hotspot within the BRCT2 domain and predicts that this substitution is likely to disturb the local structure in a manner that is comparable to other nearby pathogenic alterations (Ambry internal data; Varma AK et al. Biochemistry. 2005 Aug;44:10941-6). 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.
Counsyl RCV000112600 SCV000785274 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2017-06-22 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131349 SCV001357318 likely pathogenic Hereditary cancer-predisposing syndrome 2019-11-20 criteria provided, single submitter clinical testing This missense variant replaces phenylalanine with serine at codon 1761 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Two functional studies reported the variant protein to be loss-of-function based on a haploid cell proliferation assay (PMID: 30209399) and in yeast transcription activation assay (PMID: 19016756). This variant has been report in an individual affected with breast cancer before age 50 with family history of early-onset breast cancer (PMID: 19016756). This variant has also been reported in a multifactorial analysis with family history likelihood ratio of 6.9 (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194348 SCV001363817 likely pathogenic Hereditary breast ovarian cancer syndrome 2019-08-22 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5282T>C (p.Phe1761Ser) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) 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 251176 control chromosomes. c.5282T>C has been reported in the literature in at-least one individual affected with Hereditary Breast Cancer (Sugano_2008). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a greater than 99% probability of pathogenicity based on a transcriptional activation (TA) assay (Woods_2016). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV001194348 SCV001563384 likely pathogenic Hereditary breast ovarian cancer syndrome 2021-09-17 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112600 SCV000145437 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2003-12-23 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000112600 SCV001241683 not provided Breast-ovarian cancer, familial, susceptibility to, 1 no assertion provided in vitro

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