Submissions for variant NM_007294.4(BRCA1):c.3746C>G (p.Thr1249Ser)

gnomAD frequency: 0.00001  dbSNP: rs80357099

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485104	SCV000571437	uncertain significance	not provided	2023-02-23	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 3865C>G; Observed in individuals undergoing clinical testing for hereditary breast and ovarian cancer syndrome (Abkevich et al., 2004; Judkins et al., 2005); This variant is associated with the following publications: (PMID: 32377563, 31911673, 29884841, 31853058, 15235020, 16267036)
Ambry Genetics	RCV000562072	SCV000665876	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-20	criteria provided, single submitter	clinical testing	The p.T1249S variant (also known as c.3746C>G), located in coding exon 9 of the BRCA1 gene, results from a C to G substitution at nucleotide position 3746. The threonine at codon 1249 is replaced by serine, an amino acid with similar 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.
Invitae	RCV001359002	SCV001554862	benign	Hereditary breast ovarian cancer syndrome	2024-01-22	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV001359002	SCV002515204	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
University of Washington Department of Laboratory Medicine, University of Washington	RCV000562072	SCV003849785	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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330417	SCV004038329	uncertain significance	not specified	2023-08-07	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3746C>G (p.Thr1249Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251258 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3746C>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome without strong evidence for causality (examples: Judkins_2005, Matta_2022, Pereira_2022). These report(s) do 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. The following publications have been ascertained in the context of this evaluation (PMID: 16267036, 36329109, 35980532). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS: n=3; likely benign/benign: n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112169	SCV000144856	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing