ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.10111A>G (p.Thr3371Ala) (rs80358393)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000167810 SCV000071727 likely benign Hereditary breast and ovarian cancer syndrome 2020-10-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131701 SCV000186738 likely benign Hereditary cancer-predisposing syndrome 2018-08-23 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000034424 SCV000210697 likely benign not provided 2020-08-13 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 22703879, 27376475, 25682074, 20104584, 26580448, 26933808)
Counsyl RCV000031301 SCV000221120 likely benign Breast-ovarian cancer, familial 2 2015-02-05 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000043714 SCV000694494 likely benign not specified 2019-03-15 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.10111A>G (p.Thr3371Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-06 in 277018 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. This variant has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.5335delC, p.Gln1779fsX14; BRCA1 c.4612C>T, p.Gln1538X; BRCA1 c.3778_3779insA, p.Leu1260fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Five laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000034424 SCV000883505 likely benign not provided 2018-04-24 criteria provided, single submitter clinical testing The BRCA2 c.10111A>G; p.Thr3371Ala variant (rs80358393) has been described in individuals affected with breast cancer who also harbor a known pathogenic BRCA1 variant (see link to BIC database). This variant has also been observed in individuals with no personal or family history of cancer (Johnston 2012). It is reported in ClinVar (Variation ID: 37720) and observed in the general population at an overall frequency of 0.0007% (2/277018 alleles) in the Genome Aggregation Database. The threonine at codon 3371 is moderately conserved but computational algorithms (PolyPhen-2, SIFT) predict this variant to be tolerated. Based on available information, this variant is considered likely benign. References: BIC database: Johnston J et al. Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. Am J Hum Genet. 2012 Jul 13;91(1):97-108.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034424 SCV000888970 likely benign not provided 2019-09-16 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131701 SCV000902875 benign Hereditary cancer-predisposing syndrome 2017-02-10 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001642251 SCV001852872 uncertain significance Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034424 SCV000043240 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000031301 SCV000053906 benign Breast-ovarian cancer, familial 2 2012-02-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031301 SCV000145754 uncertain significance Breast-ovarian cancer, familial 2 2000-06-12 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353827 SCV000592312 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Thr3371Ala variant was identified in 3 of 4206 proband chromosomes (frequency: 0.001) from individuals or families with contralateral and unilateral breast cancer (Borg 2010). The variant was also previously identified by our laboratory in 1 individual with breast cancer. The p.Thr3371Ala variant was identified in the dbSNP with “Other” allele. This variant was identified in ClinVar database as likely benign by Ambry Genetics, GeneDX and Counsyl; as benign by Sharing Clinical Reports Project derived by Myriad Reports; as uncertain significance by Invitae, BIC and Biesecker laboratory ClinSeq Project NHGRI. The p.Thr3371Ala variant was identified in BIC 3x with unknown clinical importance; in BRCA Share UMD 1x and classified as unknown. The variant was not identified in NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (released March 14, 2016), GeneInsight COGR, Clinvitae, COSMIC, MutDB, LOVD Fanconi’s Anemia Mutation and ARUP Laboratories Databases. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. The p.Thr3371 residue is conserved in mammals and not in lower organism and the variant amino acid Alanine is present in chicken, increasing the likelihood that this variant does not have clinical significance. 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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