Submissions for variant NM_007294.4(BRCA1):c.4402A>C (p.Asn1468His)

gnomAD frequency: 0.00004  dbSNP: rs80357022

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112333	SCV000244361	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 = 0.0000918
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083013	SCV000076566	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162985	SCV000213473	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	RCV000758827	SCV000516630	likely benign	not provided	2019-02-22	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17924331, 22753008, 21990134, 28781887, 23704879)
Color Diagnostics, LLC DBA Color Health	RCV000162985	SCV000688495	likely benign	Hereditary cancer-predisposing syndrome	2016-11-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000428966	SCV000699143	benign	not specified	2020-12-03	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4402A>C (p.Asn1468His) 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 2e-05 in 251222 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4402A>C has been reported in the literature in individuals affected with breast and/or ovarian cancer (e.g. Judkins_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. Functional studies reported that this variant did not significantly affect transcription activation (Woods_2016, Fernandes_2019). In addition, multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, which included analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer, tumor pathology and co-segregation with disease in pedigrees, predicted this variant to be neutral (Easton 2007 and Lindor 2012). 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 (4x) / benign (2x, including ENIGMA). Based on the evidence outlined above, the variant was classified as benign.
Counsyl	RCV000112333	SCV000785854	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2017-12-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758827	SCV000887692	likely benign	not provided	2020-04-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162985	SCV002537747	likely benign	Hereditary cancer-predisposing syndrome	2022-01-13	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV000112333	SCV004817670	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-06-15	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112333	SCV000145085	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004554677	SCV004780479	benign	BRCA1-related disorder	2019-09-03	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).