Submissions for variant NM_007294.4(BRCA1):c.4327C>G (p.Arg1443Gly)

dbSNP: rs41293455

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000019245	SCV001161592	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	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 = 2.23E-06
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048522	SCV000076535	benign	Hereditary breast ovarian cancer syndrome	2024-01-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129043	SCV000172955	likely benign	Hereditary cancer-predisposing syndrome	2019-01-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000019245	SCV000195928	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-03	criteria provided, single submitter	clinical testing
Counsyl	RCV000019245	SCV000488475	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000588512	SCV000512308	likely benign	not provided	2019-05-08	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 18992264, 25556971, 28781887, 21990134, 7894491, 21447777, 23867111, 25525159, 17308087, 19369211, 26295337, 25652403, 28569743, 30765603, 33087888)
Color Diagnostics, LLC DBA Color Health	RCV000129043	SCV000683171	likely benign	Hereditary cancer-predisposing syndrome	2015-01-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588512	SCV000885070	likely benign	not provided	2020-04-18	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000588512	SCV000892186	likely benign	not provided	2018-07-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588512	SCV001133581	likely benign	not provided	2023-06-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000427206	SCV001360565	benign	not specified	2020-12-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4327C>G (p.Arg1443Gly) results in a non-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 3.2e-05 in 251364 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance.c.4327C>G has been reported in the literature in individuals affected with Breast and Ovarian Cancer (e.g. Ahmed_2012, Alsop_2012, Castilla_1994, Haffty_2009, Judkins_2005, Trujillano_2014). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported in the BIC and UMD databases respectively (BRCA1 c.3G>T, p.Met1Ile; BRCA1 c.269_281del, p.Ile90SerfsX25), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Bouwman_2013, Carvalho_2007, Sy_2009, Woods_2016, Fernandes_2019). Nine clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign, n=3, likely benign, n=6, VUS, n=1). Based on the evidence outlined above, to reflect the emerging consensus towards a benign outcome, the variant was classified as benign.
Sema4, Sema4	RCV000129043	SCV002538286	likely benign	Hereditary cancer-predisposing syndrome	2022-03-14	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000048522	SCV005205786	likely benign	Hereditary breast ovarian cancer syndrome	2024-07-16	criteria provided, single submitter	clinical testing
OMIM	RCV000019245	SCV000039533	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1994-12-01	no assertion criteria provided	literature only
Breast Cancer Information Core (BIC) (BRCA1)	RCV000019245	SCV000145056	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000048522	SCV000503551	uncertain significance	Hereditary breast ovarian cancer syndrome	2016-08-01	no assertion criteria provided	research	Found in a 37 year old female patient having exome sequencing for an unrelated indication. No known history of breast cancer. Family history of a mother with breast ancer diagnosed at 50, a maternal grandmother who died of breast cancer at age 58 and a paternal grandmother diagnosed with breast and ovarian cancer.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000427206	SCV001977968	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000427206	SCV001980596	benign	not specified		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000019245	SCV004243993	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004554606	SCV004772094	likely benign	BRCA1-related disorder	2019-03-15	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).