Submissions for variant NM_000059.4(BRCA2):c.3G>A (p.Met1Ile)

dbSNP: rs80358650

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000083102	SCV001161657	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.999736
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044328	SCV000072341	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-28	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the BRCA2 mRNA. The next in-frame methionine is located at codon 124. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29478780). ClinVar contains an entry for this variant (Variation ID: 51579). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 21769658). While this variant is expected to result in an absent protein product, possible rescue of translational initiation by the downstream methionine would lead to the disruption of the N-terminal part of the BRCA2 protein that interacts with PALB2 (residues 18-40), which is critical for BRCA2-mediated homologous recombinational DNA repair (PMID: 16793542, 22678057, 19369211). This variant disrupts the p.Met1 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14647210, 18182601, 21769658, 24156927, 25330149; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000162893	SCV000213380	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-02	criteria provided, single submitter	clinical testing	The p.M1? pathogenic mutation (also known as c.3G>A) is located in coding exon 1 of the BRCA2 gene and results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon (ATG). This mutation has been identified in one kindred with familial breast cancer in which three members were affected; two were diagnosed at age 45 and one at age 37 (Thomassen M et al. Breast Cancer Res. Treat. 2012 Apr;132(3):1009-23). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000083102	SCV000296498	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-06-04	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000083102	SCV000326954	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000083102	SCV000605705	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-01-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000083102	SCV000786194	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-03-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162893	SCV001735119	pathogenic	Hereditary cancer-predisposing syndrome	2020-11-23	criteria provided, single submitter	clinical testing	This variant results in the loss of the translation start codon of the BRCA2 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 20104584, 21769658, 28807866) and in a hereditary breast/ovarian cancer family (PMID: 21203900). This variant has also been analyzed by multifactorial analysis and classified as pathogenic based in part on segregation and tumor pathology likelihood ratios of 67.6 and 2.7, respectively (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003237421	SCV002010372	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Hauer Lab, Department Of Pediatric Oncology, Technical University Munich	RCV000162893	SCV004174262	pathogenic	Hereditary cancer-predisposing syndrome		criteria provided, single submitter	research	ACMG/AMP, PVS1, PM2, PP5
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000044328	SCV004848523	likely pathogenic	Hereditary breast ovarian cancer syndrome	2021-07-15	criteria provided, single submitter	clinical testing	The p.Met1Ile variant in BRCA2 has been reported in at least 10 individuals with BRCA2-associated cancers (Borg 2010 PMID:20104584, Thomassen 2012 PMID:21769658, Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/) and in >10 individuals with a family history of breast and ovarian cancer (HBOC) that had undergone clinical genetic testing (Konecny 2011 PMID: 21203900, Meisel 2017 PMID:28324225; Heramb 2018 PMID:29339979, Rebbeck 2018 PMID: 29446198). It has also been identified in 0.001% (1/68028) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1). This variant affects the translation initiation start codon (ATG) and is therefore predicted to disrupt translation through a variety of outcomes (no protein synthesis or the activation of an upstream translation initiation codon), though the precise effect cannot be predicted. Of note, a possible alternate initiation codon location exists downstream at codon 124, which would result in a protein that is missing 4% of the coding region. In vitro functional studies support an impact on protein function (Mesman 2018 PMID:29988080). Additionally, this variant was classified as Pathogenic on Jun 18, 2019 by the ClinGen-approved ENIGMA expert panel (Variation ID 51579). Other variants affecting this translation initiation codon have been identified in individuals with HBOC in ClinVar. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HBOC. ACMG/AMP criteria applied: PS4_Strong, PM2_Supporting, PVS1_Moderate, PS3_Supporting, PM5_Supporting.
Sharing Clinical Reports Project (SCRP)	RCV000083102	SCV000115176	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2009-07-17	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083102	SCV000145999	not provided	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044328	SCV000587525	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
CZECANCA consortium	RCV001271035	SCV001451852	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000083102	SCV004243925	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing