Submissions for variant NM_000059.4(BRCA2):c.10203G>A (p.Thr3401=)

gnomAD frequency: 0.00017  dbSNP: rs147854265

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000495047	SCV000579028	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079781	SCV000166156	benign	Hereditary breast ovarian cancer syndrome	2025-02-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000168621	SCV000167428	benign	not specified	2014-03-31	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	RCV000164133	SCV000214748	likely benign	Hereditary cancer-predisposing syndrome	2014-10-28	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000168621	SCV000602881	likely benign	not specified	2017-03-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164133	SCV000683398	likely benign	Hereditary cancer-predisposing syndrome	2015-11-17	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000164133	SCV000803166	likely benign	Hereditary cancer-predisposing syndrome	2018-05-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679151	SCV000805642	likely benign	not provided	2017-03-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679151	SCV000888973	benign	not provided	2023-01-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000168621	SCV000918997	likely benign	not specified	2021-01-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001112897	SCV001270611	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.
Illumina Laboratory Services, Illumina	RCV000495047	SCV001272117	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.
Sema4, Sema4	RCV000164133	SCV002533198	likely benign	Hereditary cancer-predisposing syndrome	2021-07-10	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492533	SCV004240286	likely benign	Breast and/or ovarian cancer	2022-10-03	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000495047	SCV001553254	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The BRCA2 p.Thr3401= variant was identified in 2 of 18,724 proband chromosomes (frequency: 0.0001) from individuals or families with hereditary breast and ovarian cancer and was present in 2 of 22,642 control chromosomes (frequency: 0.00009) from healthy individuals (Momozawa 2018, Borg 2010, Stegel 2011). The variant was identified in dbSNP (rs147854265) as “with likely benign, other allele”, ClinVar (classified as likely benign by Ambry Genetics, Color, PreventionGenetics and 6 other submitters; and as benign by GeneDx and Invitae) and LOVD 3.0 (observed 18x). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 15 of 282,140 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 7 of 24,948 chromosomes (freq: 0.0003), Other in 2 of 7202 chromosomes (freq: 0.0003), European in 5 of 128,822 chromosomes (freq: 0.00004), and South Asian in 1 of 30,504 chromosomes (freq: 0.0003); it was not observed in the Latino, Ashkenazi Jewish, East Asian or Finnish populations. The p.Thr3401= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.