Submissions for variant NM_007294.4(BRCA1):c.4816A>G (p.Lys1606Glu)

gnomAD frequency: 0.00001  dbSNP: rs80356943

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)	RCV000031193	SCV001161595	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 = 0.000266
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048668	SCV000076681	benign	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130005	SCV000184830	likely benign	Hereditary cancer-predisposing syndrome	2021-05-10	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.
GeneDx	RCV001281714	SCV000512312	likely benign	not provided	2020-10-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30765603, 32546644, 28781887, 16267036, 8531968, 15004537, 16905680, 31131967)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001281714	SCV000605892	likely benign	not provided	2021-01-15	criteria provided, single submitter	clinical testing
Counsyl	RCV000031193	SCV000785870	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-12-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130005	SCV000903167	likely benign	Hereditary cancer-predisposing syndrome	2017-03-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000436368	SCV000918792	likely benign	not specified	2024-02-09	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4816A>G (p.Lys1606Glu) 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 3.1e-05 in 1613986 control chromosomes (gnomAD v4.0.0). This frequency is not significantly higher than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (3.1e-05 vs 0.001), allowing no conclusion about variant significance. c.4816A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Fitzgerald_1996, Judkins_2005, Simard_2007). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Two independent publications spanning a decade report experimental evidence evaluating an impact on protein function, both of which demonstrate no functional impact of this variant on measures of yeast small colony phenotype assay (Coyne 2004) and a transcriptional activation assay coupled to a Bayesian hierarchical model that estimated the likelihood of pathogenicity (Woods, 2016). The following publications have been ascertained in the context of this evaluation (PMID: 15004537, 8531968, 16267036, 26206375, 15385441, 16905680, 28781887). ClinVar contains an entry for this variant (Variation ID: 37612). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000031193	SCV001140508	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130005	SCV002537786	likely benign	Hereditary cancer-predisposing syndrome	2021-02-01	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735492	SCV003838737	likely benign	Breast and/or ovarian cancer	2023-06-05	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031193	SCV000053793	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031193	SCV000145189	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	RCV000031193	SCV000591540	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing	The BRCA1 p.Lys1606Glu variant was identified in at least 9 of 111320 proband chromosomes from individuals with breast cancer or who were referred for BRCA1 screening (Fitzgerald 1996, Judkins 2005); however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. This variant was previously identified by our lab in an individual with breast cancer, and was also identified in dbSNP (ID: rs80356943) “With untested allele”, HGMD, UMD (1X as an unknown variant), and the BIC database (8X with unknown clinical importance). This residue is not conserved in mammals or lower organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735492	SCV000863630	uncertain significance	Breast and/or ovarian cancer		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004554630	SCV004715220	likely benign	BRCA1-related disorder	2022-10-12	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).