Submissions for variant NM_000059.4(BRCA2):c.7051G>A (p.Ala2351Thr)

gnomAD frequency: 0.00006  dbSNP: rs80358930

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000045128	SCV000073141	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130893	SCV000185802	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-27	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	likely benign	not provided	2020-02-26	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with early onset breast cancer or ovarian cancer (Lee 2008, Akbari 2011); This variant is associated with the following publications: (PMID: 10923033, 31131967, 30287823, 28111427, 21965345, 18284688, 25348012, 25583476)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656801	SCV000600732	uncertain significance	not provided	2023-06-14	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 21965345 (2011), 30287823 (2018), 31907386 (2020), 34218100 (2021), 33471991 (2021), and 35464868 (2022)), gastric cancer (PMID: 25583476 (2015)). The variant has also been observed in unaffected individuals (PMIDs: 30287823 (2018) and 33471991 (2021)). The frequency of this variant in the general population, 0.0002 (6/30498 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV000515244	SCV000611376	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 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, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	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.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000045128	SCV002025810	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000113696	SCV002584704	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2022-10-06	criteria provided, single submitter	clinical testing	The BRCA2 c.7051G>A (p.Ala2351Thr) missense change has a maximum subpopulation frequency of 0.020% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with breast and ovarian cancer (PMID: 18284688, 21965345) and a case-control study indicated that individuals with this variant had an increased risk of developing breast cancer with an odds ratio of 1.6 (PMID: 30287823). However, this variant has also been reported in individuals who harbored a pathogenic variant in BRCA1 or BRCA2 (UMD, NHGRI BIC databases). This variant is absent in the FLOSSIES database, which contains genetic variants from women older than 70 years of age who have never had cancer (https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000113696	SCV003806862	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2022-03-03	criteria provided, single submitter	clinical testing	ACMG classification criteria: BP4 supporting
MGZ Medical Genetics Center	RCV003607218	SCV004543914	benign	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: BP1_STR, BS1_SUP; BP5_MOD
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113696	SCV000147007	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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.