ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7040C>A (p.Pro2347Gln) (rs80358929)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045126 SCV000073139 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces proline with glutamine at codon 2347 of the BRCA2 protein (p.Pro2347Gln). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with prostate cancer (PMID: 21952622). This variant has also been observed in an individual with ovarian cancer (PMID: 22711857). However, in that individual pathogenic allele[s] were also identified, which suggests that this c.7040C>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 52254). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000167327 SCV000218177 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-29 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000657035 SCV000567076 uncertain significance not provided 2017-08-23 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7040C>A at the cDNA level, p.Pro2347Gln (P2347Q) at the protein level, and results in the change of a Proline to a Glutamine (CCA>CAA). Using alternate nomenclature, this variant would be defined as BRCA2 7268C>A. This variant has been observed in at least one breast cancer patient and at least one early-onset prostate cancer patient and was also reported to co-occur with a pathogenic BRCA1/2 variant in an individual with ovarian cancer (Kote-Jarai 2011, Warren 2011, Alsop 2012). BRCA2 Pro2347Gln was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Proline and Glutamine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Pro2347Gln occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Pro2347Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000481408 SCV000592092 uncertain significance not specified 2015-01-19 criteria provided, single submitter clinical testing
Counsyl RCV000113695 SCV000785098 uncertain significance Breast-ovarian cancer, familial 2 2017-04-19 criteria provided, single submitter clinical testing
Color RCV000167327 SCV000906461 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000481408 SCV000917007 uncertain significance not specified 2017-12-04 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7040C>A (p.Pro2347Gln) variant involves the alteration of a non-conserved nucleotide and 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). However, these predictions have yet to be functionally assessed. This variant is absent in 245898 control chromosomes (gnomAD). A publication, Alsop_2012 reports the variant in a patient that co-occurred with an unidentified pathogenic BRCA1/2 mutation. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as a "Variant of Uncertain Significance (VUS)."
Breast Cancer Information Core (BIC) (BRCA2) RCV000113695 SCV000147006 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV000657035 SCV000986843 not provided not provided no assertion provided phenotyping only Variant interpretted as Uncertain significance and reported on 09/08/2018 by GTR ID Credit Valley Hospital Department of Laboratory Medicine. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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