Submissions for variant NM_000059.4(BRCA2):c.9606G>A (p.Pro3202=)

dbSNP: rs755890067

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000495294	SCV000578579	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/).
Ambry Genetics	RCV000164400	SCV000215036	likely benign	Hereditary cancer-predisposing syndrome	2014-08-04	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.
Invitae	RCV001087565	SCV000560441	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000460818	SCV000600870	likely benign	not provided	2020-07-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000504386	SCV000695256	likely benign	not specified	2019-08-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164400	SCV000906706	likely benign	Hereditary cancer-predisposing syndrome	2017-09-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001110896	SCV001268385	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	RCV000495294	SCV001268386	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.
GeneDx	RCV000460818	SCV001939399	benign	not provided	2015-04-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535098	SCV004708656	likely benign	BRCA2-related disorder	2023-08-03	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
All of Us Research Program, National Institutes of Health	RCV000495294	SCV004846197	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-05-31	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000460818	SCV000592295	likely benign	not provided		no assertion criteria provided	clinical testing	The p.Pro3202Pro was identified in a cohort of Italian ovarian cancer patients, with frequency unspecified, as a polymorphism with no clinical significance (Minucci 2015). The variant was also identified in dbSNP (ID: rs755890067) “With Likely benign allele”, Clinvitae database (classification likely benign), the ClinVar database (classified as likely benign by Ambry Genetics and Invitae), UMD (13X with ”unclassified variant”), co-occurring with a pathogenic BRCA1 variant (c.4183C>T, p.Gln1395X); and in the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 6 of 66734 chromosomes (frequency: 0.00008) from a population of European (Non-Finnish) individuals, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. It was not identified in East Asian, Other, African, Latino, South Asian, and European (Finnish) populations in EXAC. The p.Pro3202Pro 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. In addition, 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as likely benign.