ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.10202C>T (p.Thr3401Met) (rs55853199)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001083163 SCV000071738 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV000132503 SCV000187597 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-28 criteria provided, single submitter clinical testing The p.T3401M variant (also known as c.10202C>T), located in coding exon 26 of the BRCA2 gene, results from a C to T substitution at nucleotide position 10202. The threonine at codon 3401 is replaced by methionine, an amino acid with similar properties. This alteration has been detected in a Polish family with two cases of breast cancer, one case of ovarian cancer, and one case of colon cancer (Górski B et al. Am. J. Hum. Genet. 2000 Jun;66:1963-8). In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet., 2018 04;14:e1007352). In a study of 2984 breast cancer cases, 4376 prostate cancer cases, and 7545 controls this alteration was observed with an allele frequency of 0.000384 in Latinos (Haiman CA et al. PLoS Genet., 2013 Mar;9:e1003419). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000435257 SCV000512406 likely benign not specified 2017-04-07 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000435257 SCV000538500 uncertain significance not specified 2016-06-23 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 2 LB, 2 VUS, reported in 1 proband
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000755872 SCV000600455 uncertain significance not provided 2020-06-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282963 SCV000883503 uncertain significance none provided 2020-03-05 criteria provided, single submitter clinical testing The BRCA2 c.10202C>T; p.Thr3401Met variant (rs55853199) is reported in the literature in at least one family affected with breast, ovarian, and colon cancer (Gorski 2000). This variant is reported in ClinVar (Variation ID: 51053), and found in the general population with an overall allele frequency of 0.002% (6/282206 alleles) in the Genome Aggregation Database. The threonine at codon 3401 is weakly conserved, but computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. Given the lack of clinical and functional data, the significance of the p.Thr3401Met variant is uncertain at this time. References: Gorski B et al. Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer. Am J Hum Genet. 2000 Jun;66(6):1963-8.
Color Health, Inc RCV000132503 SCV000903035 benign Hereditary cancer-predisposing syndrome 2016-11-21 criteria provided, single submitter clinical testing
Mendelics RCV000077247 SCV001139289 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000755872 SCV001334484 uncertain significance not provided 2020-02-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000435257 SCV001338629 uncertain significance not specified 2020-04-06 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.10202C>T (p.Thr3401Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 305166 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.10202C>T has been reported in the literature in individuals affected with Breast and Ovarian Cancer (Gorski_2000, Gorski_2006, Cunningham_2014, Haiman_2013, Wong-Brown_2015, Melloni_2017) and CRC (Deihimi_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign n=4, VUS n=4). Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute of Human Genetics, University of Leipzig Medical Center RCV000077247 SCV001428759 uncertain significance Breast-ovarian cancer, familial 2 2019-11-08 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077247 SCV000109044 likely benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077247 SCV000145765 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000077247 SCV001549612 uncertain significance Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing The BRCA2 p.Thr3401Met variant was not identified in the literature nor was it identified in the UMD-LSDB. The variant was identified in dbSNP (ID: rs55853199) as "With other allele", ClinVar (classified as benign by Color; as likely benign by Invitae, GeneDx and SCRP; as uncertain significance by five submitters), and in LOVD 3.0 (2x as VUS) .The variant was identified in control databases in 6 of 276618 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24014 chromosomes (freq: 0.00004), Latino in 1 of 34344 chromosomes (freq: 0.00003), European in 4 of 126344 chromosomes (freq: 0.00003), while the variant was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Thr3401 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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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