ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6986C>T (p.Pro2329Leu) (rs80358925)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000167790 SCV000073115 likely benign Hereditary breast and ovarian cancer syndrome 2020-10-29 criteria provided, single submitter clinical testing
GeneDx RCV000045102 SCV000210641 likely benign not specified 2017-03-01 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 RCV000163085 SCV000213588 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-06 criteria provided, single submitter clinical testing The p.P2329L variant (also known as c.6986C>T), located in coding exon 12 of the BRCA2 gene, results from a C to T substitution at nucleotide position 6986. The proline at codon 2329 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in a patient with breast cancer diagnosed at age 38 from a cohort of 220 high-risk Asian breast cancer patients who were tested with a multi-gene panel (Wong ESY et al. NPJ Genom Med, 2016 Jan;1:15003). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000045102 SCV000600728 uncertain significance not specified 2017-06-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586419 SCV000695016 uncertain significance not provided 2016-12-19 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.6986C>T (p.Pro2329Leu) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 118176 control chromosomes. This variant has been reported in BrC individual with no information on co-segregation provided. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance and one lab classified it as likely benign, all without evidence to independently evaluate. Taken together, due to lack of clinical information and functional data, this variant is classified as VUS.
Counsyl RCV000077392 SCV000786113 uncertain significance Breast-ovarian cancer, familial 2 2018-02-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163085 SCV000906928 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-30 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 2329 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant protein moderately increases the sensitivity to PARP inhibitors in mammalian cells when compared with the wild-type protein (PMID: 32444794). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 26221963, 28828701, 29263802). This variant has also been identified in 1/250074 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP) RCV000077392 SCV000109189 likely benign Breast-ovarian cancer, familial 2 2012-04-23 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077392 SCV000146985 uncertain significance Breast-ovarian cancer, familial 2 2002-06-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354293 SCV001548872 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Pro2329Leu variant was identified in 2 of 1158 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer (Wong 2015, Wong 2016). The variant was also identified in dbSNP (ID: rs80358925) as "With Uncertain significance, other allele", ClinVar (classified as likely benign by GeneDx and SCRP; as uncertain significance by Ambry Genetics, Counsyl, Invitae, BIC and two clinical laboratories), UMD-LSDB (1x as unclassified variant), and in BIC Database (3x with unknown significance). The variant was not identified in COGR, Cosmic, MutDB, LOVD 3.0, ARUP Laboratories, or Zhejiang University Database. The variant was identified in control databases in 1 of 245002 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 111266 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Pro2329 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs 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. This variant is classified as a variant of uncertain significance.

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