Submissions for variant NM_000059.4(BRCA2):c.1189_1190insTTAG (p.Gln397fs)

dbSNP: rs397515635

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000238897	SCV000323962	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-10-18	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Invitae	RCV000043755	SCV000071768	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln397Leufs*25) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs397515635, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with clinical features of hereditary breast and ovarian cancer syndrome (PMID: 16644204, 22006311, 26681312, 26787237, 27989354, 29961768). This variant is also known as 1417insTTAG and 1418insTTAG. ClinVar contains an entry for this variant (Variation ID: 51080). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131278	SCV000186246	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-09	criteria provided, single submitter	clinical testing	The c.1189_1190insTTAG pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from an insertion of 4 nucleotides at position 1189, causing a translational frameshift with a predicted alternate stop codon (p.Q397Lfs*25). This alteration has been previously reported in multiple individuals with a personal and/or family history of early-onset breast, ovarian, and/or pancreatic cancer (Lalloo F et al. Eur. J. Cancer. 2006 May;42(8):1143-50; Haffty BG et al. Ann. Oncol. 2009 Oct;20(10):1653-9; Walsh T et al. Proc. Natl. Acad. Sci. USA. 2011 Nov;108(44):18032-7; Yurgelun MB et al. Genet. Med. 2019 01;21(1):213-223) as well as in identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39(5):593-620). Of note, this alteration is also designated as 1417ins4 and 1417insTTAG in some published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000238897	SCV000326510	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000238897	SCV000489480	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-10-10	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000043755	SCV000588077	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-20	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000043755	SCV000605807	pathogenic	Hereditary breast ovarian cancer syndrome	2016-12-23	criteria provided, single submitter	clinical testing	The p.Gln397fs variant in BRCA2 has been reported in at least 5 individuals with BRCA2-associated cancers (Lalloo 2006, Walsh 2011, Susswein 2015, Breast Cancer Information Core (BIC) database), and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein?s ami no acid sequence beginning at position 397 and leads to a premature termination codon 25 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on October 18, 2016 by t he ClinGen-approved ENIGMA expert panel (ClinVar SCV000323962.1). In summary, th is variant meets criteria to be classified as pathogenic for HBOC in an autosoma l dominant manner.
Color Diagnostics, LLC DBA Color Health	RCV000131278	SCV000688698	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-14	criteria provided, single submitter	clinical testing	This variant inserts 4 nucleotides in exon 10 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast cancer (PMID: 16644204, 26787237), ovarian cancer (PMID: 22006311, 30322717), pancreatic cancer (PMID: 29961768), and prostate cancer (PMID: 27989354). This variant has been identified in 1/250170 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000043755	SCV000694518	pathogenic	Hereditary breast ovarian cancer syndrome	2017-01-19	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.1189_1190insTTAG (p.Gln397Leufs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.1257delT/p.Cys419fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 120790 control chromosomes. This variant has been reported in multiple affected individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003891520	SCV000805648	pathogenic	BRCA2-related condition	2024-01-09	criteria provided, single submitter	clinical testing	The BRCA2 c.1189_1190insTTAG variant is predicted to result in a frameshift and premature protein termination (p.Gln397Leufs*25). This variant has been reported in families with breast and ovarian cancer (Lalloo et al., 2006. PubMed ID: 16644204; Walsh et al., 2011. PubMed ID: 22006311; Susswein et al., 2016. PubMed ID: 26681312). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar by an expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/51080/?new_evidence=true). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679153	SCV000887751	pathogenic	not provided	2020-01-14	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in individuals and families affected with breast and/or ovarian in the published literature (PMID: 30322717 (2018), 22006311 (2011), 16644204 (2006)). Based on the available information, this variant is classified as pathogenic.
Baylor Genetics	RCV003460559	SCV004216044	pathogenic	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679153	SCV004565005	pathogenic	not provided	2023-03-21	criteria provided, single submitter	clinical testing	The BRCA2 c.1189_1190insTTAG; p.Gln397LeufsTer25 variant (rs397515635) is reported in the literature in individuals with hereditary breast and ovarian cancer syndrome (Evans 2022, Susswein 2016, Walsh 2011). This variant is also reported in ClinVar (Variation ID: 51080). It is only found on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by inserting four nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Evans DG et al. High likelihood of actionable pathogenic variant detection in breast cancer genes in women with very early onset breast cancer. J Med Genet. 2022 Feb;59(2):115-121. PMID: 33758026. Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32. PMID: 26681312. Walsh T et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7. PMID: 22006311.
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000043755	SCV000587582	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research