ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9843A>G (p.Pro3281=) (rs11571832)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000112817 SCV000578008 benign Breast-ovarian cancer, familial 2 2017-06-29 reviewed by expert panel curation Synonymous substitution variant, with low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; and frequency 0.0019 (African), derived from ExAC (2014-12-17).
Invitae RCV000045906 SCV000073919 benign Hereditary breast and ovarian cancer syndrome 2020-12-06 criteria provided, single submitter clinical testing
GeneDx RCV000176715 SCV000167424 benign not specified 2014-05-06 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.
Michigan Medical Genetics Laboratories,University of Michigan RCV000112817 SCV000196030 benign Breast-ovarian cancer, familial 2 2014-11-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000163358 SCV000213893 likely benign Hereditary cancer-predisposing syndrome 2014-10-24 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000176715 SCV000228419 likely benign not specified 2015-01-16 criteria provided, single submitter clinical testing
Baylor Genetics RCV000476571 SCV000541065 benign Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163358 SCV000684094 likely benign Hereditary cancer-predisposing syndrome 2015-07-30 criteria provided, single submitter clinical testing
Counsyl RCV000112817 SCV000784932 likely benign Breast-ovarian cancer, familial 2 2017-02-07 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000112817 SCV000145722 uncertain significance Breast-ovarian cancer, familial 2 2003-10-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358433 SCV001554162 likely benign not provided no assertion criteria provided clinical testing The BRCA2 p.Pro3281= variant was identified in 1 of 800 proband chromosomes (frequency: 0.001) from Nigerian individuals with breast cancer, unselected for age of onset and family history (Fackenthal 2012). The variant was also identified in dbSNP (ID: rs11571832) “With Uncertain significance, other allele”, ClinVar (classified with conflicting interpretations of pathogenicity; classified as benign by GeneDx, Michigan Medical Genetics Labs (U of Michigan), Baylor Miraca Genetics Labs and Invitae; likely benign by Ambry Genetics and Emory Genetics; and uncertain significance by BIC), Clinivitae (6X), LOVD 3.0 (3X) and BIC database (1X). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, BIC Database, ARUP Laboratories, and Zhejiang Colon Cancer Database. The variant was identified in control databases in 41 of 276990 chromosomes at a frequency of 0.0001 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: African in 33 of 24028 chromosomes (frequency: 0.001), Other in 1 of 6458 chromosomes (frequency: 0.0002), Latino in 6 of 34410 chromosomes (frequency: 0.0002), European Non-Finnish in 1 of 126516 chromosomes (frequency: 0.000008), . The p.Pro3281= variant is not expected to have clinical significance because it does not result in a change of amino acid and occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.

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