Submissions for variant NM_000059.4(BRCA2):c.1889C>T (p.Thr630Ile)

gnomAD frequency: 0.00012  dbSNP: rs80358479

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031349	SCV000244427	benign	Breast-ovarian cancer, familial, susceptibility to, 2	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 = 0.000000121
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082203	SCV000071930	benign	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000193487	SCV000210571	likely benign	not specified	2017-10-25	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.
Ambry Genetics	RCV000162511	SCV000212902	benign	Hereditary cancer-predisposing syndrome	2014-11-19	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.
Counsyl	RCV000031349	SCV000220713	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-09-19	criteria provided, single submitter	literature only
Genetic Services Laboratory, University of Chicago	RCV000193487	SCV000246806	likely benign	not specified	2015-07-17	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034433	SCV000602820	likely benign	not provided	2023-03-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000034433	SCV000694581	benign	not provided	2016-08-22	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.1889C>T (p.Thr630Ile) variant causes a missense change involving a non-conserved nucleotide with 3/5 in silico tools predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was found in the large, broad control population, ExAC, with an allele frequency of 21/116384 (1/5543), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA2 variant of 1/1333. Multiple publications have cited the variant in affected individuals, in particular, reputable databases have cited the variant to co-occur with multiple pathogenic BRCA2 variants, 1 - c.6468_6469delTC (p.Gln2157IlefsX18), 2 - c.4829_4830delTG (p.Val1610fs), 1 - c.276dupA (p.Gln92fs), and BRCA1 variants, 1 - c.4936delG (Val1646fs), 1 - c.3700_3704delGTAAA (p.Val1234fs), c.5263dupC (p.Ser1755fs). In additional, multiple reputable databases/clinical laboratories and publications cite the variant as "likely benign/benign." Therefore, the variant of interest has been classified as Benign.
Color Diagnostics, LLC DBA Color Health	RCV000162511	SCV000910579	likely benign	Hereditary cancer-predisposing syndrome	2015-07-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000031349	SCV001269323	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001111739	SCV001269324	uncertain significance	Fanconi anemia complementation group D1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
CeGaT Center for Human Genetics Tuebingen	RCV000034433	SCV001961398	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	BRCA2: BP4
Sema4, Sema4	RCV000162511	SCV002533272	benign	Hereditary cancer-predisposing syndrome	2021-01-19	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV001082203	SCV004014921	benign	Hereditary breast ovarian cancer syndrome	2023-03-09	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000031349	SCV004016892	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-07	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735526	SCV004240297	likely benign	Breast and/or ovarian cancer	2023-04-27	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000193487	SCV004242849	benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000193487	SCV004848657	benign	not specified	2022-06-12	criteria provided, single submitter	clinical testing	The p.Thr630Ile variant in BRCA2 is classified as benign because it has been identified in 0.4% (43/9876) of Ashkenazi Jewish chromosomes, including 1 homozygote, by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034433	SCV000043200	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Sharing Clinical Reports Project (SCRP)	RCV000031349	SCV000053954	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2006-12-19	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031349	SCV000145972	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000193487	SCV000591778	benign	not specified		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000034433	SCV000778649	likely benign	not provided	2018-02-28	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000162511	SCV000787920	likely benign	Hereditary cancer-predisposing syndrome	2017-12-01	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735526	SCV000863664	benign	Breast and/or ovarian cancer		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000193487	SCV002035472	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000193487	SCV002038185	benign	not specified		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532434	SCV004740221	benign	BRCA2-related disorder	2019-10-03	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).