Submissions for variant NM_000059.4(BRCA2):c.742G>A (p.Ala248Thr)

gnomAD frequency: 0.00014  dbSNP: rs55854959

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001087231	SCV000073222	benign	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131381	SCV000186357	likely benign	Hereditary cancer-predisposing syndrome	2019-04-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CSER _CC_NCGL, University of Washington	RCV000148438	SCV000190137	uncertain significance	Breast neoplasm	2014-06-01	criteria provided, single submitter	research	Low GERP score may suggest that this variant may belong in a lower pathogenicity class
GeneDx	RCV000586272	SCV000210254	uncertain significance	not provided	2023-10-11	criteria provided, single submitter	clinical testing	Observed in individuals with breast cancer, but also in unaffected controls (Olopade et al., 2003; Fackenthal et al., 2005; Haffty et al., 2006; Maxwell et al., 2015; Momozawa et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 970G>A; This variant is associated with the following publications: (PMID: 15744044, 12491487, 26773734, 28814288, 30287823, 15983021, 22034289, 24728327, 27300552, 25637381, 25503501, 11030417, 24504028, 33471991, 33233347)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586272	SCV000600748	likely benign	not provided	2022-12-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120387	SCV000695062	likely benign	not specified	2022-01-10	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.742G>A (p.Ala248Thr) 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 2.3e-05 in 298566 control chromosomes (gnomAD, Bodian_2014, Fackenthal_2005, Momozawa_2018), predominantly at a frequency of 0.00031 within the African or African-American subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.742G>A has been reported in the literature in individuals affected with breast cancer (example: Gao_2000, Haffty_2006, Maxwell_2015, Dorling_2021), however, it was also found in healthy controls (example: Bodian_2014, Momozawa_2018, Dorling_2021, FLOSSIES database). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. This variant was found co-occurring with another pathogenic BRCA2 variant via internal testing (BRCA2 c.5164_5165delAG, p.Ser1722fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters have assessed the variant since 2014: five have classified the variant as of uncertain significance, three as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000131381	SCV000910963	likely benign	Hereditary cancer-predisposing syndrome	2016-03-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000114118	SCV001138978	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000114118	SCV001482843	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-01-08	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798238	SCV002043454	uncertain significance	Breast and/or ovarian cancer	2020-11-02	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120387	SCV002066884	uncertain significance	not specified	2021-12-20	criteria provided, single submitter	clinical testing	This sequence change has been previously described in individuals with breast cancer and reportedly unaffected individuals (PMIDs: 15744044, 12491487, 30287823, 15983021, 22034289, 24728327). This sequence change has been described in the gnomAD database with a frequency of 0.028% in the African subpopulation (dbSNP rs55854959). The p.Ala248Thr change affects a poorly conserved amino acid residue located in a domain of the BRCA2 protein that is known to be functional. The p.Ala248Thr substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Ala248Thr change remains unknown at this time.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000114118	SCV004031168	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-05-31	criteria provided, single submitter	clinical testing	The BRCA2 c.742G>A (p.Ala248Thr) missense change has a maximum subpopulation frequency of 0.028% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in an individual with a personal history of breast cancer (PMID: 15744044). 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.
ITMI	RCV000120387	SCV000084539	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA2)	RCV000114118	SCV000147649	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	1997-11-13	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732621	SCV000805761	uncertain significance	BRCA2-related disorder	2024-04-02	no assertion criteria provided	clinical testing	The BRCA2 c.742G>A variant is predicted to result in the amino acid substitution p.Ala248Thr. This variant has been reported in 8 heterozygous individuals within the gnomAD population database and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/52326/). This variant has been reported in a Nigerian individual with breast cancer who also had an additional intronic variant in their BRCA2 gene, however its significance was unclear (Table 1, Fackenthal et al 2005, PubMed ID: 15744044). More recent studies have identified this variant in at least one individual from the NHLBI ESP database and also classified its significance as uncertain (Amendola et al. 2015, PubMed ID: 25637381) while another identified it within a healthy, ancestrally diverse cohort (Bodian et al. 2014, PubMed ID: 24728327). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355487	SCV001550390	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The BRCA2 p.Ala248Thr variant was identified in 5 of 14324 proband chromosomes (frequency: 0.0003) from individuals or families with breast cancer and was identified in 1 of 1510 chromosomes from healthy individuals (Amendola 2015, Fackenthal 2005, Fackenthal 2012, Haffty 2005). The variant was also identified in dbSNP (ID: rs55854959) as "With Uncertain significance allele", ClinVar (classified as likely benign by Invitae; as uncertain significance by Ambry Genetics, GeneDx, BIC and three other clinical laboratories), Cosmic (2x), MutDB, LOVD 3.0 (2x), UMD-LSDB (3x as unclassified variant), and BIC (4x as unknown significance). The variant was not identified in the COGR, ARUP Laboratories, or Zhejiang University databases. The variant was identified in control databases in 9 of 276698 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 8 of 23984 chromosomes (freq: 0.0003) and European in 1 of 126390 chromosomes (freq: 0.000008), but not in the “Other”, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ala248 residue is not conserved in mammals and 5 of 5 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 4 of 4 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.
BRCAlab, Lund University	RCV000114118	SCV004244025	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing