Submissions for variant NM_007294.4(BRCA1):c.4081A>C (p.Met1361Leu)

gnomAD frequency: 0.00001  dbSNP: rs80357218

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112244	SCV000244353	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-08-10	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000196
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048437	SCV000076450	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162982	SCV000213470	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.
Counsyl	RCV000112244	SCV000487985	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-12-08	criteria provided, single submitter	clinical testing
GeneDx	RCV001284397	SCV000521417	likely benign	not provided	2018-06-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21990134, 18951461, 22753008, 15235020, 17924331, 15829246)
Color Diagnostics, LLC DBA Color Health	RCV000162982	SCV000688464	likely benign	Hereditary cancer-predisposing syndrome	2017-07-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000438101	SCV000699106	likely benign	not specified	2022-02-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4081A>C (p.Met1361Leu) 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 8e-06 in 250858 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4081A>C has been reported in the literature in an individual affected with breast cancer (Lee_2008). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Multiple studies using multifactorial likelihood models have classified this variant as having a neutral impact (Easton_2007, Lindor_2012, Fernandes_2019, Parsons_2019) (IARC class I). To our knowledge, no other experimental evidence demonstrating an impact on protein function has been reported. Six other submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign (n=4) / benign (n=2; including ENIGMA). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284397	SCV001470175	likely benign	not provided	2020-07-11	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162982	SCV002538258	likely benign	Hereditary cancer-predisposing syndrome	2020-08-21	criteria provided, single submitter	curation
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112244	SCV000144960	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing