Submissions for variant NM_007294.4(BRCA1):c.3640G>A (p.Glu1214Lys)

gnomAD frequency: 0.00006  dbSNP: rs80356923

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)	RCV000112142	SCV000244344	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 = 0.000000000689
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080705	SCV000076279	benign	Hereditary breast ovarian cancer syndrome	2024-01-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162552	SCV000212962	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	RCV000433388	SCV000515872	benign	not specified	2017-09-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color Diagnostics, LLC DBA Color Health	RCV000162552	SCV000683118	likely benign	Hereditary cancer-predisposing syndrome	2015-06-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000433388	SCV000699049	benign	not specified	2022-05-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3640G>A (p.Glu1214Lys) 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. However, comparative evolutionary approach for classifying the variant using mammalian BRCA1 sequences as performed by Burk-Herrick_2005 shows that this variant has low oncogenic score. The variant allele was found at a frequency of 9.9e-05 in 251288 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (9.9e-05 vs 0.001), allowing no conclusion about variant significance. c.3640G>A, has been reported in the literature in individuals affected with Breast and Ovarian Cancer in one family where it did not segregate with disease (example, Zuhlke_2004). Large multifactorial likelihood-ratio model study that included cosegregation, co-occurrence, and logistic regression analyses shows that this variant has high odds in favor of benign effect (Easton_2007). Similarly, in another multifactorial probability model study, this variant was shown to have very low odds in favor of causality (Lindor et al 2012). These data do not allow any conclusion about variant significance. At-least two co-occurrences with other pathogenic variant(s) have been reported in the BIC database and also observed at our laboratory (BIC-BRCA2 c.6833_6837delTCTTA, p.Ile2278fs; our laboratory-BRCA2 c.2095C>T, p.Q699X), providing supporting evidence for a benign role. Eight clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000162552	SCV000803148	likely benign	Hereditary cancer-predisposing syndrome	2018-05-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000590363	SCV000806937	likely benign	not provided	2017-02-27	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000433388	SCV000966375	likely benign	not specified	2018-05-07	criteria provided, single submitter	clinical testing	p.Glu1214Lys in exon 10A of BRCA1: This variant is classified as likely benign b ecause it did not segregate with disease in one family and since it has been ide ntified in 0.03% (12/3438)) of Latino chromosomes by the Genome Aggregation Data base (gnomAD, http://gnomAD.broadinstitute.org; dbSNP rs80356923). In addition, this variant was classified as benign on Aug 10, 2015 by the ClinGen-approved (E NIGMA) expert panel (ClinVar 54948). Computational prediction tools and conserva tion analysis suggest that the p.Glu1214Lys variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. ACMG /AMP Criteria applied: BS4, BP4.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000433388	SCV001156832	likely benign	not specified	2018-07-31	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112142	SCV000144819	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000433388	SCV000587325	benign	not specified	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353446	SCV000591458	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Glu1214Lys variant was identified in one individual with ovarian cancer and one family with hereditary prostate cancer; however, control chromosomes from healthy individuals were not included in these studies (Akbari 2011, Zuhlke 2004). The variant was also identified in dbSNP (ID: rs80356923) ‚ With untested allele‚Äù, LOVD, COSMIC, UMD (8X as a neutral variant), and the BIC database (9X with unknown clinical importance). This residue is conserved in mammals but not across lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. One in silico study by Tram (2013) suggests that the variant may affect protein binding to neighbouring nucleotides; however, two other in silico studies using a multifactorial likelihood-ratio model predict this variant to be neutral or likely not pathogenic (Easton 2007, Lindor 2012). However, Myriad has found this variant in trans with a known deleterious mutation and classify it as a polymorphism (personal communication). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000590363	SCV000778744	likely benign	not provided	2017-01-03	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000590363	SCV001741357	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000433388	SCV001959557	benign	not specified		no assertion criteria provided	clinical testing