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

dbSNP: rs80356905

Total submissions: 8

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 Diagnostics, LLC DBA Color Health	RCV000131349	SCV001357318	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-08-29	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). This variant has been reported to impact BRCA1 function in a homology-directed repair assay, haploid human cell proliferation assay and yeast transcription activation assays (PMID: 10811118, 20516115, 29884841, 30209399). This variant has been reported in three individuals affected with breast cancer and/or ovarian (PMID: 19016756, 34072659; Color internal data) and a multifactorial analysis has reported co-occurrence and family history likelihood ratios for pathogenicity of 1.067 and 6.917, respectively (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	2022-06-22	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 10811118, 20516115, 28781887, 30209399, 30765603). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 55505). This missense change has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 19016756). This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1761 of the BRCA1 protein (p.Phe1761Ser).
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV001194348	SCV004228256	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-10-12	criteria provided, single submitter	curation	PS3, PM2_supporting, PP3. According to the ACMG standard criteria we chose these criteria: PS3 (strong pathogenic): Findlay et al., 2018: LOF; Fernandes et al., 2019: fclass 5; Lee et al., 2010: strong functional effect, PM2 (supporting pathogenic): absent from controls, PP3 (supporting pathogenic): REVEL: 0.872 ; PRIOR: 0.66
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