Submissions for variant NM_007294.4(BRCA1):c.3655G>A (p.Glu1219Lys)

dbSNP: rs80356921

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048274	SCV000076287	benign	Hereditary breast ovarian cancer syndrome	2024-10-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129819	SCV000184633	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-24	criteria provided, single submitter	clinical testing	The p.E1219K variant (also known as c.3655G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 3655. The glutamic acid at codon 1219 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV001569902	SCV001794070	likely benign	not provided	2021-04-12	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31131967, 23704879, 15385441)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129819	SCV003846329	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001569902	SCV004219367	uncertain significance	not provided	2023-01-03	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/251304 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported as a variant of uncertain significance (PMID: 16267036 (2005)). Additionally, studies utilizing prediction models to assess the variant have reported it both as likely benign (PMID: 31131967 (2019)) and as deleterious (PMIDs: 15385441 (2004) and 23704879 (2013)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV000112148	SCV004817773	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1219 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. A multifactorial analysis has reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant and family history of 1.1026 and 0.0753, respectively (PMID: 31131967). This variant has been identified in 1/251304 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000129819	SCV006063567	uncertain significance	Hereditary cancer-predisposing syndrome	2025-02-10	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1219 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. Multifactorial analyses have reported likelihood ratios (LR) for pathogenicity based on co-occurrence with a pathogenic variant and personal and family history, reaching a combined LR of 0.5579 for one carrier (PMID: 31131967, 31853058). This variant has been identified in 1/251304 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005406785	SCV006070931	uncertain significance	not specified	2025-03-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3655G>A (p.Glu1219Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251304 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3655G>A has been reported in the literature as a VUS in at least one individual affected with breast cancer with a positive family history of cancers related to Hereditary Breast And Ovarian Cancer Syndrome, although segregation was not established (e.g. Bhai_2021). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one co-occurrence with a pathogenic variant has been reported (BRCA1 c.5109T>G, p.Tyr1703X; BIC database), providing supporting evidence for a benign role. A report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as uncertain significance/likely benign in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34326862, 31112341). ClinVar contains an entry for this variant (Variation ID: 54956). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112148	SCV000144826	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing