Submissions for variant NM_007294.4(BRCA1):c.3691T>C (p.Phe1231Leu)

gnomAD frequency: 0.00013  dbSNP: rs41293451

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195391	SCV000076295	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131521	SCV000186515	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV001281713	SCV000209955	likely benign	not provided	2020-12-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25348012, 26295337, 23704879, 15385441, 28873162, 30400234)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001281713	SCV000296415	likely benign	not provided	2023-02-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048282	SCV000699058	likely benign	not specified	2024-05-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3691T>C (p.Phe1231Leu) 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 allele was found at a frequency of 3.2e-05 in 251286 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant was also observed in two individuals in the Flossies database. c.3691T>C has been reported in the literature in individuals affected with breast cancer (e.g. Pal_2015, Zabala_2018, Guindalini_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with a pathogenic variant has been observed in our lab (BRCA2 c.518delG, p.Gly173ValfsX12), providing supporting evidence for a benign role.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: 26287763, 30400234, 35264596). ClinVar contains an entry for this variant (Variation ID: 37541). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000195391	SCV000839250	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131521	SCV000902939	benign	Hereditary cancer-predisposing syndrome	2016-02-24	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131521	SCV002538229	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-01	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000131521	SCV003851437	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).
Sharing Clinical Reports Project (SCRP)	RCV000031122	SCV000053720	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2010-02-25	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031122	SCV000144836	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2003-12-23	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004554626	SCV004760470	likely benign	BRCA1-related disorder	2019-03-21	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).