Total submissions: 17
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001083163 | SCV000071738 | likely benign | Hereditary breast ovarian cancer syndrome | 2024-01-05 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV000132503 | SCV000187597 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-10-25 | 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 identified in multiple individuals diagnosed with breast and/or ovarian cancer (Górski B et al. Am. J. Hum. Genet. 2000 Jun;66:1963-8; Abdel-Razeq H et al. Front Oncol, 2022 Mar;12:673094). 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 variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). 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. |
Gene |
RCV000755872 | SCV000512406 | likely benign | not provided | 2021-04-20 | criteria provided, single submitter | clinical testing | This variant is associated with the following publications: (PMID: 26332594, 26843898, 10788334, 31131967) |
Laboratory for Molecular 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 | 2022-02-16 | criteria provided, single submitter | clinical testing | |
ARUP Laboratories, |
RCV000755872 | SCV000883503 | uncertain significance | not 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 Diagnostics, |
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, susceptibility to, 2 | 2019-05-28 | criteria provided, single submitter | clinical testing | |
Ce |
RCV000755872 | SCV001334484 | uncertain significance | not provided | 2020-02-01 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000435257 | SCV001338629 | uncertain significance | not specified | 2023-06-29 | 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 five 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 cancers (e.g. (Gorski_2000, Gorski_2006, Cunningham_2014, Haiman_2013, Wong-Brown_2015, Melloni_2017 Abdel-Razeq_2021, Guo_2020) as well as prostate cancer(Fei_2021) and colorectal cancer (Deihimi_2017), without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34290354, 24504028, 28591715, 34709755, 20223018, 10788334, 31837001, 23555315, 28569218, 25682074). Eleven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=7) or benign (n=1)/likely benign (n=3). Based on the evidence outlined above, the variant was classified as uncertain significance. |
Institute of Human Genetics, |
RCV000077247 | SCV001428759 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 2 | 2019-11-08 | criteria provided, single submitter | clinical testing | |
Sema4, |
RCV000132503 | SCV002533197 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-09-15 | criteria provided, single submitter | curation | |
Center for Genomic Medicine, |
RCV000435257 | SCV004242589 | likely benign | not specified | 2024-02-06 | criteria provided, single submitter | clinical testing | |
Sharing Clinical Reports Project |
RCV000077247 | SCV000109044 | likely benign | Breast-ovarian cancer, familial, susceptibility to, 2 | 2012-05-01 | no assertion criteria provided | clinical testing | |
Breast Cancer Information Core |
RCV000077247 | SCV000145765 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 2 | 2002-05-29 | no assertion criteria provided | clinical testing | |
Department of Pathology and Laboratory Medicine, |
RCV000077247 | SCV001549612 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 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. | |
Zotz- |
RCV000077247 | SCV004171591 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 2 | 2023-11-24 | no assertion criteria provided | clinical testing |