Submissions for variant NM_000059.4(BRCA2):c.9353T>C (p.Met3118Thr)

gnomAD frequency: 0.00005  dbSNP: rs56204128

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000045797	SCV000073810	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131368	SCV000186344	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-25	criteria provided, single submitter	clinical testing	The p.M3118T variant (also known as c.9353T>C), located in coding exon 24 of the BRCA2 gene, results from a T to C substitution at nucleotide position 9353. The methionine at codon 3118 is replaced by threonine, an amino acid with similar properties. This alteration was reported in a Japanese breast cancer family (Katagiri T et al. J. Hum. Genet., 1998;43:42-8). It was also reported in a Japanese female diagnosed with osteosarcoma of the leg at age 16 and bilateral breast cancers at ages 32 and 34; her mother was diagnosed with breast cancer at age 45. This case report did not mention whether the patient had undergone TP53 germline testing (Kuno T et al. Breast Cancer, 1999 Jan;6:51-54). This alteration was detected in a cohort of 88 African American individuals with a personal and/or family history of breast and/or ovarian cancer (McDonald JT et al. PLoS One, 2022 Oct;17:e0273835). This alteration was also reported in a patient with breast cancer who was also found to carry a pathogenic mutation in the PALB2 gene (Cheng JM et al. Breast Cancer Res Treat, 2023 Jun;199:389-397). In one study, this variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). Using a computational method that produces a probabilistic likelihood ratio predictive of whether a missense variant impairs protein function, this alteration is predicted to be neutral (Karchin R et al. Cancer Inform, 2008 Apr;6:203-16). This amino acid position is not well conserved in available vertebrate species, and threonine is the reference amino acid in other 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.
CSER _CC_NCGL, University of Washington	RCV000148437	SCV000190136	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	RCV001508342	SCV000568497	uncertain significance	not provided	2023-07-17	criteria provided, single submitter	clinical testing	Observed in individuals with personal and/or family history of breast cancer, including a patient who also harbored a pathogenic variant in PALB2 (Katagiri et al., 1998; Kuno et al., 1999; Dorling et al., 2021; Cheng et al., 2023); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 9581T>C; This variant is associated with the following publications: (PMID: 12491487, 24055113, 19043619, 25637381, 9609997, 31131967, 37002487, 12228710, 33471991, 23555315, 11091690)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001508342	SCV000600855	uncertain significance	not provided	2022-07-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131368	SCV000906440	likely benign	Hereditary cancer-predisposing syndrome	2016-02-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000484041	SCV000917018	uncertain significance	not specified	2023-08-22	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9353T>C (p.Met3118Thr) results in a non-conservative amino acid change located in the OB3 (oligonucleotide binding) fold (IPR015188) of 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 1.6e-05 in 251326 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant was also reported in 1/2559 African American women, over 70 years of age with no history of cancer (FLOSSIES database). c.9353T>C has been reported in the literature in individuals affected with breast cancer (Katagiri_1998, Dorling_2021, McDonald_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with one other pathogenic variant has been reported (BRCA1 c.2940delA [p.Pro981HisfsX19], BIC database), providing supporting evidence for a benign role. 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: 25637381, 33471991, 24055113, 23555315, 19043619, 9609997, 11091690, 36315513, 12491487). Eight ClinVar submitters have assessed the variant since 2014: six classified the variant as uncertain significance and two as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV001508342	SCV001714440	uncertain significance	not provided	2021-01-29	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131368	SCV002532024	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-06	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000031815	SCV002584570	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-23	criteria provided, single submitter	clinical testing	The BRCA2 c.9353T>C (p.Met3118Thr) missense change has a maximum subpopulation frequency of 0.025% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant has been reported in an individual with a personal history of breast cancer and osteosarcoma and a family history of breast cancer (PMID: 9609997), however this individual did not undergo germline evaluation of other potential predisposing genes including TP53 (PMID: 11091690). It has also been reported in one individual in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). 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. In summary, the evidence currently available is insufficient to determine the role of this variant in hereditary breast and ovarian cancer syndrome and/or Fanconi anemia. It has therefore been classified as of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003982854	SCV004800081	uncertain significance	BRCA2-related condition	2024-02-21	criteria provided, single submitter	clinical testing	The BRCA2 c.9353T>C variant is predicted to result in the amino acid substitution p.Met3118Thr. This variant was reported in an individual with breast cancer and osteosarcoma and a family history of breast cancer (Katagiri et al 1998. PubMed ID: 9609997). Of note, there was no mention of additional genetic testing beyond BRCA1 and BRCA2 analysis, for this family. A bioinformatics analysis utilizing protein likelihood ratios predicted that the p.Met3118 variant would have a neutral impact on protein function (Supplementary Table 1, Karchin R et al 2008. PubMed ID: 19043619). This variant was interpreted as a variant of uncertain significance in a study of incidental findings in participants’ exomes (Table S1, Dorschner et al 2013. PubMed ID: 24055113; Amendola et al 2015. PubMed ID: 25637381). This variant has been reported twice in the Breast Cancer Information Core database with uncertain clinical significance (https://research.nhgri.nih.gov/bic/). This variant is reported in 0.025% of alleles in individuals of African descent in gnomAD and has conflicting interpretations in the ClinVar database, ranging from likely benign to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/38232/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Sharing Clinical Reports Project (SCRP)	RCV000031815	SCV000054423	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2011-03-18	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031815	SCV000147615	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing