ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7051G>A (p.Ala2351Thr) (rs80358930)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045128 SCV000073141 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-11-26 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 2351 of the BRCA2 protein (p.Ala2351Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs80358930, ExAC 0.02%). This variant has been observed in several individuals affected with breast and/or ovarian cancer as well as unaffected controls (PMID: 18284688, 21965345, 30287823). However, it was reported to co-occur with a pathogenic allele in the BRCA1 gene in one individual in the Breast Cancer Information Core database (PMID: 10923033), which suggests that this c.7051G>A substitution in BRCA2 was not the primary cause of disease in that individual. ClinVar contains an entry for this variant (Variation ID: 52256). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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 RCV000130893 SCV000185802 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-10 criteria provided, single submitter clinical testing The p.A2351T variant (also known as c.7051G>A), located in coding exon 13 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7051. The alanine at codon 2351 is replaced by threonine, an amino acid with similar properties. This alteration has been reported with a carrier frequency of 4 in 7,051 unselected breast cancer patients and 4 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun. 2018 10;9:4083). This alteration has also been reported in 1 of 1345 ovarian cancer patients (Akbari MR et al. J. Med. Genet. 2011 Nov;48:783-6) and in a cohort of 1469 early-onset breast cancer patients (Lee E et al. Breast Cancer Res. 2008 Mar;10:R19). 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 RCV000656801 SCV000210414 uncertain significance not provided 2017-10-10 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7051G>A at the cDNA level, p.Ala2351Thr (A2351T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). Using alternate nomenclature, this variant would be defined as BRCA2 7279G>A. This variant has been reported in at least one individual with early onset breast cancer and one individual with ovarian cancer (Lee 2008, Akbari 2011). BRCA2 Ala2351Thr was observed at an allele frequency of 0.02% (6/30654) in individuals of South Asian ancestry in large population cohorts (Lek 2016). Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ala2351Thr occurs at a position that is not conserved and is located within the FANCD2 binding domain (Uniprot). 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 Ala2351Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656801 SCV000600732 uncertain significance not provided 2019-07-08 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515244 SCV000611376 uncertain significance Familial cancer of breast; Breast-ovarian cancer, familial 2; Fanconi anemia, complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer 2; Glioma susceptibility 3; Tracheoesophageal fistula 2017-05-23 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765134 SCV000896360 uncertain significance Familial cancer of breast; Breast-ovarian cancer, familial 2; Fanconi anemia, complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer 2; Glioma susceptibility 3 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130893 SCV000910879 likely benign Hereditary cancer-predisposing syndrome 2017-02-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212257 SCV001467863 uncertain significance not specified 2020-12-04 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7051G>A (p.Ala2351Thr) 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 6.7e-05 in 298156 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer Syndrome (6.7e-05 vs 0.00075), allowing no conclusion about variant significance. c.7051G>A has been reported in the literature in individuals affected with breast or ovarian cancer (example: Akbari_2011, Lee_2008, Momozawa_2018, Park_2020) as well as in controls (Momozawa_2018). These reports however, do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported in UMD and NHGRI BIC databases (BRCA2 c.1723A>T, p.Lys575X; BRCA1 c.2411_2412delAG, p.Gln804Leufs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=7) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113696 SCV000147007 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 RCV001353685 SCV000592094 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Ala2351Thr variant was identified by Akbari (2011) in an individual with ovarian cancer. The variant was also identified in dbSNP (ID: rs80358930) “With unknown allele”, and in the BIC database (4X with unknown clinical importance). The variant was also identified the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 7 of 120970 chromosomes (frequency: 0.0000) (or 4 South Asian, 1 East Asian, 2 European (Non-Finnish) individuals) and none from a population of Other/African/Latino/European (Finnish) individuals; COSMIC, the ClinVar database (classified as a uncertain significance by BIC, classified as uncertain significance by Ambry Genetics, and classification not provided by Invitae) and UMD (3X as a 3-unclassified variant). In UMD the variant was identified with a co-occurring pathogenic BRCA2 variant (c.1723A>T, p.Lys575X), increasing the likelihood that the p.Ala2351Thr variant does not have clinical significance. In addition, Myriad classifies this variant as a polymorphism (personal communication).The BRCA2 IARC database notes that there is a weak/null probability of creating a de novo splice donor at nt #7046 and a weak/null probability to create a de novo splice acceptor at nt #7063. The p.Ala2351 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact of the variant amino acid on the protein; this information is not very predictive of pathogenicity. 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 unknown significance.

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