Submissions for variant NM_007294.4(BRCA1):c.4255G>C (p.Glu1419Gln)

dbSNP: rs80357309

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112305	SCV000244357	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 = 0.000152
Labcorp Genetics (formerly Invitae), Labcorp	RCV001078624	SCV000076516	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162984	SCV000213472	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	RCV000588065	SCV000293656	likely benign	not provided	2019-05-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22949387, 18951461, 21120943, 22753008, 17924331, 21990134)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588065	SCV000699125	likely benign	not provided	2017-03-07	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.4255G>C (p.Glu1419Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 121396 control chromosomes. However, multiple publications cite the variant with a classification of "likely neutral." In addition, multiple reputable databases/clinical laboratories cite the variant with a classification of "benign/likely benign/uncertain significance." In addition, a poster abstract (IUBMB 2015) cites a functional study that showed the variant to act comparable to wild type functions for transcriptional activation ability and PALB2 interaction. One recent functional study (Woods_2016) showed preserved transcriptional activity and no deleterious effects on the BRCA1-PALB2 protein-protein interaction in the presence of this variant. Taken together, this variant is classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000162984	SCV000903861	benign	Hereditary cancer-predisposing syndrome	2016-03-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588065	SCV001133579	likely benign	not provided	2023-03-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000112305	SCV004817687	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-02	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112305	SCV000145042	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-11-25	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000112305	SCV000591501	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing	The p.Glu1419Gln variant has been identified in 2/114310 proband chromosomes of individuals with breast cancer and/or ovarian cancer; although, no control chromosomes were tested to establish the variant's frequency in the general population (Caux-Moncoutier 2011, Judkins 2005a, Lindor 2011, Millot 2012). The variant is listed in dbSNP database (ID#:rs80357309) as coming from a "clinical source" but no frequency information was provided, and so the prevalence of this variant in the population is not known. The p.Glu1419 residue is conserved in mammals, but computational analyses (PolyPhen, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In addition, this variant is listed in the BIC (x1) database, as well as in the UMD mutation database to co-occur with a pathogenic mutation in BRCA2 c.3744_3747delTGAG (p.Ser1248ArgfsX10), increasing the likelihood that p.Glu1419Gln is benign. In summary, based on the above information, the p.Arg3370Arg variant is classified as predicted benign.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735479	SCV000863616	likely benign	Breast and/or ovarian cancer	2012-08-27	no assertion criteria provided	clinical testing