Submissions for variant NM_007294.4(BRCA1):c.427G>A (p.Glu143Lys)

gnomAD frequency: 0.00004  dbSNP: rs80356991

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031161	SCV000244359	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 = 0.0000109
Labcorp Genetics (formerly Invitae), Labcorp	RCV000588563	SCV000076523	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV001719704	SCV000210075	likely benign	not provided	2021-02-09	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11698567, 18936166, 21990134, 17924331, 25085752, 22753008, 24312913, 23161852, 16267036, 28408614, 26689913, 15385441, 30287823, 30219179, 30617304, 33087888)
Ambry Genetics	RCV000162967	SCV000213455	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000159939	SCV000538455	uncertain significance	not specified	2016-06-23	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 3 B/LB, including expert panel
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000159939	SCV000699128	likely benign	not specified	2024-07-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.427G>A (p.Glu143Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 251024 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (8.4e-05 vs 0.001), allowing no conclusion about variant significance. c.427G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. The variant has been functionally evaluated and showed similar to wild-type activity in an HDR assay and intermediate activity in a less specific Single strand annealing (SSA) assay (Towler, 2013, Lu, 2015 and Starita, 2018). The HDR assay qualifies as a standardized gold-standard assay on the basis of the updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) Working Group (Brnich_2019). ClinGen SVI now recognizes benign functional evidence as sufficient for likely benign (Tavtigian_2018). The following publications have been ascertained in the context of this evaluation (PMID: 16267036, 15385441, 21990134, 17924331, 11698567, 23161852, 18936166, 26689913, 27300552, 30219179). ClinVar contains an entry for this variant (Variation ID: 37580). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl	RCV000031161	SCV000786473	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2018-05-14	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000159939	SCV000885069	likely benign	not specified	2019-01-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162967	SCV000902846	likely benign	Hereditary cancer-predisposing syndrome	2015-08-20	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798032	SCV002043445	likely benign	Breast and/or ovarian cancer	2022-07-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504841	SCV002796513	likely benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2022-03-10	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000159939	SCV004026818	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031161	SCV000053761	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2010-11-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031161	SCV000145475	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV002250474	SCV002520914	uncertain significance	Familial cancer of breast		no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004758611	SCV005364547	likely benign	BRCA1-related disorder	2024-03-09	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).