Submissions for variant NM_007294.4(BRCA1):c.2155A>G (p.Lys719Glu)

gnomAD frequency: 0.00021  dbSNP: rs80357147

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen	RCV000111777	SCV004101419	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-10	reviewed by expert panel	curation	The c.2155A>G variant in BRCA1 is a missense variant predicted to cause substitution of Lysine by Glutamic acid at amino acid 719 (p.Lys719Glu). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth >=20) or gnomAD v3.1 (non-cancer subset, read depth >=20) is 0.0003 in the African/African American population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.0001) for BS1, and below the BA1 threshold (>0.001) (BS1 met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0.01, score threshold <0.1) (BP1_Strong met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.0000515 (based on Family History LR= 0.0000515), below the thresholds for very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID 31131967). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BS1, BP1_Strong, BP5_Very strong).
Invitae	RCV000203646	SCV000075745	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131665	SCV000186693	likely benign	Hereditary cancer-predisposing syndrome	2022-09-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV000587133	SCV000210123	uncertain significance	not provided	2023-10-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast or pancreatic cancer (PMID: 26287763, 30883245); Also known as 2274A>G; This variant is associated with the following publications: (PMID: 16267036, 15385441, 28135145, 26287763, 30883245, 30603682, 15343273)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855631	SCV000698924	uncertain significance	not specified	2023-05-18	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2155A>G (p.Lys719Glu) 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 4.8e-05 in 251194 control chromosomes, predominantly at a frequency of 0.00062 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (4.8e-05 vs 0.001), allowing no conclusion about variant significance. However, the variant was reported in 5/2559 African American women (i.e. with an allele frequency of about 0.001), who were older than age 70, and have never had cancer (in the FLOSSIES database), suggesting that the variant might be a benign polymorphism. c.2155A>G, has been reported in the literature in individuals affected with or without a family history of Breast and Ovarian Cancer (Judkins_2005, Pal_2015, Abe_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. 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: 30883245, 16267036, 26287763, 15385441). Fourteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=6) and VUS (n=). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mendelics	RCV000203646	SCV000839273	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000203646	SCV000890982	likely benign	Hereditary breast ovarian cancer syndrome	2021-08-26	criteria provided, single submitter	clinical testing	The BRCA1 c.2155A>G (p.Lys719Glu) missense change has a maximum subpopulation frequency of 0.080% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/17-41245393-T-C). Seven of seven in silico tools predict a benign effect of this variant on protein function (BP4), however to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in two individuals with a family history of pancreatic cancer, one of which also had a family history of breast and colon cancer (PMID: 30883245). In addition, this variant has been reported in five women older than 70 years of age who have never had cancer (BS2_supporting; https://whi.color.com/variant/17-41245393-T-C). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS2_supporting, BP4.
Color Diagnostics, LLC DBA Color Health	RCV000131665	SCV000903737	likely benign	Hereditary cancer-predisposing syndrome	2015-04-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587133	SCV001133515	likely benign	not provided	2020-10-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000111777	SCV001140582	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587133	SCV001472034	uncertain significance	not provided	2019-10-13	criteria provided, single submitter	clinical testing	The BRCA1 c.2155A>G; p.Lys719Glu variant (rs80357147), is reported in the literature in at least one individual affected with breast cancer, though it was not demonstrated to be disease-causing (Pal 2015). This variant is found in the African population with an overall allele frequency of 0.08% (20/24898 alleles) in the Genome Aggregation Database, and it is reported in ClinVar (Variation ID: 37452). The lysine at codon 719 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Lys719Glu variant is uncertain at this time. References: Pal T et al. A high frequency of BRCA mutations in young black women with breast cancer residing in Florida. Cancer. 2015 Dec 1;121(23):4173-80.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798026	SCV002043428	uncertain significance	Breast and/or ovarian cancer	2020-11-04	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000855631	SCV002071895	uncertain significance	not specified	2021-10-06	criteria provided, single submitter	clinical testing	This sequence change does not appear to have been previously described in individuals with BRCA1-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.080% in the African subpopulation (dbSNP rs80357147). The p.Lys719Glu change affects a poorly conserved amino acid residue located in a domain of the BRCA1 protein that is known to be functional. The p.Lys719Glu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Lys719Glu change remains unknown at this time.
Sema4, Sema4	RCV000131665	SCV002538098	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-27	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000131665	SCV003849456	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).
PreventionGenetics, part of Exact Sciences	RCV003914878	SCV004734871	uncertain significance	BRCA1-related condition	2023-12-20	criteria provided, single submitter	clinical testing	The BRCA1 c.2155A>G variant is predicted to result in the amino acid substitution p.Lys719Glu. This variant has been also reported in at least one individual undergoing hereditary cancer genetic testing (Table 2, Judkins et al. 2005. PubMed ID 16267036). It has also been reported in two individuals without a personal history of cancer (Table A3, Abe et al. 2019. PubMed ID 30883245). This variant is reported in 0.080% of alleles in individuals of African descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37452/). This variant occurs within a region of the BRCA1 gene that is predicted to be tolerant to variation (Table 2, Dines et al. 2020. PubMed ID: 31911673). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111777	SCV000144312	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000587133	SCV000778761	uncertain significance	not provided	2018-02-26	no assertion criteria provided	clinical testing