Submissions for variant NM_007294.4(BRCA1):c.3722C>A (p.Ser1241Tyr)

dbSNP: rs80357143

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000048302	SCV000076315	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-08-24	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 1241 of the BRCA1 protein (p.Ser1241Tyr). 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: 16267036). ClinVar contains an entry for this variant (Variation ID: 54979). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000130833	SCV000185730	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-24	criteria provided, single submitter	clinical testing	The p.S1241Y variant (also known as c.3722C>A), located in coding exon 9 of the BRCA1 gene, results from a C to A substitution at nucleotide position 3722. The serine at codon 1241 is replaced by tyrosine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000112164	SCV000489028	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-08-03	criteria provided, single submitter	clinical testing
GeneDx	RCV001719802	SCV000521141	likely benign	not provided	2018-05-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 16267036, 15385441, 25722345, 17100994)
Color Diagnostics, LLC DBA Color Health	RCV000130833	SCV001340475	uncertain significance	Hereditary cancer-predisposing syndrome	2020-08-26	criteria provided, single submitter	clinical testing	This missense variant replaces serine with tyrosine at codon 1241 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with breast and/or ovarian cancer (PMID: 16267036). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002228165	SCV002511774	uncertain significance	not specified	2022-04-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3722C>A (p.Ser1241Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251278 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3722C>A has been reported in the literature in individual(s) affected with Hereditary Breast And Ovarian Cancer Syndrome (Judkins_2005). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000130833	SCV002538235	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-10	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130833	SCV003849951	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001719802	SCV004219374	uncertain significance	not provided	2023-06-14	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMID: 16267036 (2005)). It has been identified in a study of possible variants which may alter phosphorylation patterns of BRCA1/BRCA2 (PMID: 23704879 (2013)). Additionally, it has also been identified in a study of BRCA1 and BRCA2 regions without essential functions that tolerate variation (PMID: 31911673 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112164	SCV000144850	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000112164	SCV004244030	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing