Submissions for variant NM_007294.4(BRCA1):c.463C>G (p.Gln155Glu)

gnomAD frequency: 0.00001  dbSNP: rs80357180

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)	RCV000083209	SCV000244366	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 = 0.0000389
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079530	SCV000076627	benign	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162968	SCV000213456	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	RCV000758835	SCV000516831	likely benign	not provided	2021-03-31	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17924331, 21990134, 15235020, 22753008)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758835	SCV000887704	benign	not provided	2018-04-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162968	SCV000903496	benign	Hereditary cancer-predisposing syndrome	2016-08-02	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492389	SCV004240270	likely benign	Breast and/or ovarian cancer	2023-04-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000083209	SCV004818450	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-30	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000083209	SCV000115283	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000083209	SCV000145590	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353810	SCV000591272	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Gln155Glu variant was identified in 1 of 121052 proband chromosomes (frequency: 0.00) from individuals or families with hereditary breast and ovarian cancer (Easton 2007). The variant was also identified in dbSNP (ID: rs#80357180) “With other, untested allele”, LOVD (3X as "Predicted neutral)", ClinVar database, the BIC database (3 X with unknown clinical importance), and UMD (3 X as an unknown variant). The variant was classified as a benign variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports). Multiple functional studies have classified the variant as benign (Abkevich 2004, Easton 2007, Lindor 2012, Millot 2012). In addition, the variant was identified with a co-occurring pathogenic BRCA1 variant (p.Arg1443X), increasing the likelihood that the p.Gln155Glu variant does not have clinical significance (Judkins 2005). The p.Gln155 residue is not conserved in mammals and the variant amino acid Glutamic Acid (Glu) is present in cows increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.