Submissions for variant NM_000059.4(BRCA2):c.9672dup (p.Tyr3225fs)

gnomAD frequency: 0.00001  dbSNP: rs80359773

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000114151	SCV000301407	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics	RCV000130631	SCV000185507	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-23	criteria provided, single submitter	clinical testing	The c.9672dupA pathogenic mutation, located in coding exon 26 of the BRCA2 gene, results from a duplication of A at nucleotide position 9672, causing a translational frameshift with a predicted alternate stop codon (p.Y3225Ifs*30). This alteration has been reported in multiple individuals and families with breast and/or ovarian cancer (van der Hout AH et al. Hum. Mutat. 2006 Jul;27:654-66; Reitsma W et al. Eur. J. Cancer 2013 Jan;49(1):132-41; Tea MK et al. Maturitas 2014 Jan;77(1):68-72; De Talhouet S et al. Sci Rep, 2020 04;10:7073). Further, this alteration was reported in trans with a likely pathogenic BRCA2 missense variant in a patient diagnosed with Fanconi anemia at 2 months of age, who later died of metastatic glioblastoma multiforme at age 4 (Dodgshun AJ et al. Cancer Genet. 2016 209(1-2):53-6). This alteration has also been detected in conjunction with another BRCA2 mutation in cells derived from a patient with Fanconi anemia (Howlett NG et al. Science 2002 Jul;297(5581):606-9; Feng Z et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Jan;108(2):686-91). Of note, this alteration is also designated as 9900insA in 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. As such, this alteration is interpreted as a disease-causing mutation. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000114151	SCV000196029	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197712	SCV000255257	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr3225Ilefs*30) in the BRCA2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 194 amino acid(s) of the BRCA2 protein. This variant is present in population databases (rs80359773, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer, medulloblastoma, and Fanconi anemia (PMID: 12065746, 16683254, 24156927, 29753700). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 9900insA. ClinVar contains an entry for this variant (Variation ID: 126217). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects BRCA2 function (PMID: 12065746). This variant disrupts a region of the BRCA2 protein in which other variant(s) (p.Tyr3308*) have been determined to be pathogenic (PMID: 17026620, 18593900, 18607349, 22711857). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000114151	SCV000328160	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000372727	SCV000329588	pathogenic	not provided	2022-03-31	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: cell line with this variant exhibited sensitivity to MMC exposure, increased IR induction of foci (present in both cytoplasm and nucleus) and absent FANCD2/BRCA2 complex in chromatin (Wang 2004); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants are considered pathogenic by a well-established clinical consortium and/or database.; Also known as c.9900dupA; This variant is associated with the following publications: (PMID: 24301060, 28152038, 24156927, 14559878, 16683254, 16115142, 25447315, 25452441, 15689453, 24312913, 11597388, 15645491, 22921157, 26846091, 26740091, 22720145, 29922827, 29446198, 29753700, 30720243, 30291343, 32341426, 30787465, 31076742, 35216584, 12065746, 15199141, 10733923, 9126738)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000197712	SCV000605805	pathogenic	Hereditary breast ovarian cancer syndrome	2016-10-28	criteria provided, single submitter	clinical testing	The p.Tyr3225fs variant in BRCA2 has been reported in the heterozygous state in >30 individuals with BRCA2-associated cancers and in the compound heterozygous s tate in 1 individual with Fanconi anemia (Howlett 2002, Tea 2014, Hout 2006, Dru sedau 2013, Karami 2013, Breast Cancer Information Core (BIC) database). This va riant was absent from large population studies. This variant is predicted to cau se a frameshift, which alters the protein?s amino acid sequence beginning at pos ition 3225 and leads to a premature termination codon 30 amino acids downstream. Heterozygous loss of function of the BRCA2 gene is an established disease mecha nism in hereditary breast and ovarian cancer (HBOC). In summary, this variant me ets criteria to be classified as pathogenic for HBOC in an autosomal dominant ma nner.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000197712	SCV000695261	pathogenic	Hereditary breast ovarian cancer syndrome	2021-02-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9672dupA (p.Tyr3225IlefsX30) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant allele was found at a frequency of 4e-06 in 249832 control chromosomes (gnomAD and publication). c.9672dupA has been reported in the literature in multiple individuals affected with breast cancer and/or ovarian cancer (Couch_2015, Rebbeck_2018, BIC database). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 11 ClinVar submitters, including one expert panel (ENIGMA), (evaluation after 2014) cite the variant as pathogenic (n=10) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000114151	SCV000743528	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-10	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000114151	SCV000744792	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000130631	SCV000803165	pathogenic	Hereditary cancer-predisposing syndrome	2018-05-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000372727	SCV000889186	pathogenic	not provided	2022-06-17	criteria provided, single submitter	clinical testing	The BRCA2 c.9672dup (p.Tyr3225Ilefs*30) frameshift variant (also known as c.9672_9673insA and 9900insA) alters the translational reading frame of the BRCA2 mRNA and is predicted to cause the premature termination of BRCA2 protein synthesis. Although it is located in the last exon of BRCA2 and is not expected to undergo nonsense-mediated decay, the variant removes the last 194 residues of the BRCA2 protein including the RAD51-interaction region involved in recombination-mediated DNA repair (PMID: 17515903 (2007)). The frequency of this variant in the general population, 0.000004 (1/249592 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 32341426 (2020), 25452441 (2015), 25103822 (2014), 24156927 (2014)), as well as Fanconi anemia (PMIDs: 26740091 (2016), 22720145 (2012), 12065746 (2002)). Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000130631	SCV000911347	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-10-20	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in codon 3225 in exon 27 of the BRCA2 gene, creating a frameshift and premature translation stop signal in the last coding exon. This variant is also known as 9900insA and c.9672_9673insA in the literature. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. This variant is expected to disrupt the RAD51 binding domain that has been reported to be essential for homologous recombination and DNA repair (PMID: 17515903). Cell lines that are compound heterozygous for this variant and a known pathogenic BRCA2 truncation variant produced a truncated protein consistent with truncation in exon 27 (PMID: 12065746) and exhibited hypersensitivity to mitomycin C and other DNA damaging agents (PMID: 12065746, 16920162). This variant also has been reported in multiple individuals with personal or family history of breast and/or ovarian cancer (PMID: 16683254, 24156927, 25452441, 27153395, Color internal data). This variant has also been reported in three individuals who are compound heterozygous with a pathogenic BRCA2 covariant and affected with Fanconi anemia (PMID: 12065746, 22720145, 26740091). An external laboratory has reported the associated cancer histories of multiple carriers of this variant are inconsistent with known BRCA2 pathogenic variants (https://myriad-web.s3.amazonaws.com/publications/74925948-ACMG%202017%20Mundt%20variant%20classification%20Presented.pdf). This variant has been identified in 1/249592 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this rare variant has been observed in multiple individuals and families affected with BRCA2-related phenotypes. Although additional studies are necessary to determine the role of this variant in disease and penetrance conclusively, this variant is classified as Likely Pathogenic based on the available evidence.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000372727	SCV001762267	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000114151	SCV002581551	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-11-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004529911	SCV004119359	pathogenic	BRCA2-related disorder	2023-07-20	criteria provided, single submitter	clinical testing	The BRCA2 c.9672dupA variant is predicted to result in a frameshift and premature protein termination (p.Tyr3225Ilefs*30). This variant has been reported in the heterozygous state in multiple individuals with breast and/or ovarian cancer (van der Hout et al. 2006. PubMed ID: 16683254; Karami et al. 2013. PubMed ID: 24312913; Tea et al. 2014. PubMed ID: 24156927; Couch et al. 2014. PubMed ID: 25452441; Rebbeck et al. 2018. PubMed ID: 29446198; Haer-Wigman et al. 2019. PubMed ID: 30291343). This variant has also been reported in the compound heterozygous or homozygous state in individuals with Fanconi anemia (Howlett et al. 2002. PubMed ID: 12065746; Barber et al. 2005. PubMed ID: 16115142). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32972321-T-TA) and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/126217/). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV003460795	SCV004213675	pathogenic	Familial cancer of breast	2024-01-15	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000372727	SCV004563568	pathogenic	not provided	2023-11-10	criteria provided, single submitter	clinical testing	The BRCA2 c.9672dup; p.Tyr3225IlefsTer30 variant (rs80359773), also known as 9900insA, is reported in multiple individuals and families with hereditary breast and ovarian cancer syndrome and found compound heterozygous in at least one individual with Fanconi anemia (de Jonge 2019, Howlett 2002, Verhoog 2001). This variant is classified as pathogenic by an expert panel in the ClinVar Database (Variation ID: 126217). It is only found on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. This variant results in a premature termination codon in the last exon of the BRCA2 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated BRCA2 protein. Based on available information, this variant is considered to be pathogenic. References: de Jonge MM et al. Germline BRCA-Associated Endometrial Carcinoma Is a Distinct Clinicopathologic Entity. Clin Cancer Res. 2019 Dec 15;25(24):7517-7526. PMID: 31492746. Howlett NG et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science. 2002 Jul 26;297(5581):606-9. PMID: 12065746. Verhoog LC et al. Large regional differences in the frequency of distinct BRCA1/BRCA2 mutations in 517 Dutch breast and/or ovarian cancer families. Eur J Cancer. 2001 Nov;37(16):2082-90. PMID: 11597388.
All of Us Research Program, National Institutes of Health	RCV000114151	SCV004846215	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-02-24	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in codon 3225 in exon 27 of the BRCA2 gene, creating a frameshift and premature translation stop signal in the last coding exon. This variant is also known as 9900insA and c.9672_9673insA in the literature. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. This variant is expected to disrupt the RAD51 binding domain that has been reported to be essential for homologous recombination and DNA repair (PMID: 17515903). Cell lines that are compound heterozygous for this variant and a known pathogenic BRCA2 truncation variant produced a truncated protein consistent with truncation in exon 27 (PMID: 12065746) and exhibited hypersensitivity to mitomycin C and other DNA damaging agents (PMID: 12065746, 16920162). This variant also has been reported in multiple individuals with personal or family history of breast and/or ovarian cancer (PMID: 16683254, 24156927, 25452441, 27153395, Color internal data). This variant has also been reported in three individuals who are compound heterozygous with a pathogenic BRCA2 covariant and affected with Fanconi anemia (PMID: 12065746, 22720145, 26740091). An external laboratory has reported the associated cancer histories of multiple carriers of this variant are inconsistent with known BRCA2 pathogenic variants (https://myriad-web.s3.amazonaws.com/publications/74925948-ACMG%202017%20Mundt%20variant%20classification%20Presented.pdf). This variant has been identified in 1/249592 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this rare variant has been observed in multiple individuals and families affected with BRCA2-related phenotypes. Although additional studies are necessary to determine the role of this variant in disease and penetrance conclusively, this variant is classified as Likely Pathogenic based on the available evidence.
OMIM	RCV000009922	SCV000030143	pathogenic	Fanconi anemia complementation group D1	2002-07-26	no assertion criteria provided	literature only
Breast Cancer Information Core (BIC) (BRCA2)	RCV000114151	SCV000147696	pathogenic	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	RCV001353641	SCV000592302	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Tyr3225IlefsX30 variant was identified in individuals with hereditary breast and ovarian cancer (Karami 2013, Vos 2014) in the Netherlands populations and in Fanconi Anemia patients (Barber 2005, Howlett 2002, Lee 2014, Offit 2003, Reid 2005¬, Wang 2004), although no frequency data was given. The variant was also identified in dbSNP (ID: rs80359773) as “With Pathogenic allele”, Clinvitae database (pathogenic, Invitae), ARUP Laboratories BRCA Mutations Database (as definitely pathogenic), the ClinVar database (pathogenic, by multiple submitters), GeneInsight COGR database (unclassified) the BIC database (4x with unknown clinical importance), and UMD (3x with a “causal” classification). The c.9672dupA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 3225 and leads to a premature stop codon at position 3254. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000114151	SCV000733341	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000372727	SCV001905702	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000372727	SCV001956712	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000372727	SCV002035341	pathogenic	not provided		no assertion criteria provided	clinical testing