Submissions for variant NM_000059.4(BRCA2):c.4876_4877del (p.Asn1626fs)

dbSNP: rs80359470

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031510	SCV000282396	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044510	SCV000072523	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn1626Serfs*12) 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 (rs80359470, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and prostate cancer (PMID: 11179017, 21952622, 23524863, 24556621, 26787237, 28008555). This variant is also known as c.4874_4875delAA, 4877delAA, 5102delAA, and 5104delAA. ClinVar contains an entry for this variant (Variation ID: 37929). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131079	SCV000186009	pathogenic	Hereditary cancer-predisposing syndrome	2024-08-20	criteria provided, single submitter	clinical testing	The c.4876_4877delAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 4876 and 4877, causing a translational frameshift with a predicted alternate stop codon (p.N1626Sfs*12). This mutation has been described in multiple families with breast, ovarian, melanoma, and/or prostate cancer (Lubinski J et al. Fam Cancer, 2004;3:1-10; Audeh MW et al. Lancet, 2010 Jul;376:245-51; Zhang S et al. Gynecol Oncol, 2011 May;121:353-7; Sandhu SK et al. Ann Oncol, 2013 May;24:1416-8; Leongamornlert D et al. Br. J. Cancer, 2014 Mar;110:1663-72; Song H et al. Hum Mol Genet, 2014 Sep;23:4703-9; Meric-Bernstam F et al. Ann Oncol, 2016 05;27:795-800; Rummel SK et al. Breast Cancer Res Treat, 2017 Aug;164:593-601; Na R et al. Eur Urol, 2017 05;71:740-747; Afghahi A et al. Clin Cancer Res, 2017 07;23:3365-3370; Pritzlaff M et al. Breast Cancer Res Treat, 2017 02;161:575-586; Mijuskovic M et al. Br J Cancer, 2018 07;119:96-104; Gröbner SN et al. Nature, 2018 03;555:321-327; Zafeiriou Z et al. Eur Urol, 2019 01;75:184-192; Lovejoy LA et al. Genes (Basel), 2020 12;11; Dorling et al. N Engl J Med. 2021 02;384:428-439; Lattimore V et al. Breast Cancer Res Treat, 2021 Feb;185:583-590). Of note, this alteration is also designated as 5102delAA, 5104delAA, 4877delAA, c.4876_4877del, and c.4874_4875delAA 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 or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000160293	SCV000210757	pathogenic	not provided	2020-07-07	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 5102delAA or 5104delAA; This variant is associated with the following publications: (PMID: 28503720, 24082139, 29684080, 26681312, 28087643, 30720243, 23524863, 23242139, 11179017, 24556621, 21952622, 26787237, 17148771, 21324516, 15131399, 22006311, 28008555, 30340782, 29489754, 31325073, 29915322, 27989354, 31447099)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768595	SCV000219343	pathogenic	Breast and/or ovarian cancer	2015-08-12	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031510	SCV000267772	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160293	SCV000296684	pathogenic	not provided	2023-06-15	criteria provided, single submitter	clinical testing	The BRCA2 c.4876_4877del (p.Asn1626Serfs*12) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals affected with ovarian cancer (PMIDs: 11179017 (2001), 36169650 (2022)), breast cancer (PMIDs: 28503720 (2017), 33302456 (2020), 33113089 (2021)), prostate cancer (PMIDs: 27989354 (2017), 29915322 (2018), 30340782 (2019), 32853339 (2021)), renal cell carcinoma (PMID: 35441217 (2022)), acute lymphoblastic leukemia (ALL) (PMID: 29489754 (2018)), and colorectal cancer (PMID: 34761457 (2022)). It has been reported in individuals with breast cancer as well as in unaffected controls in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). The frequency of this variant in the general population, 0.000008 (2/249578 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031510	SCV000327099	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031510	SCV000488854	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-07-06	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000044510	SCV000605802	pathogenic	Hereditary breast ovarian cancer syndrome	2021-07-15	criteria provided, single submitter	clinical testing	The p.Asn1626SerfsX12 variant in BRCA2 has been reported in >20 individuals with BRCA2-associated cancers (Risch 2001 PMID:11179017, Kote-Jarai 2011 PMID:21952622, Gonzalez-Garay 2013 PMID:24082139, Leongamornlert 2014 PMID:24556621, Meric-Bernstam 2016 PMID:26787237, Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/). This variant has also been identified in 0.003% (2/67992) European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1). This frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1626 and leads to a premature termination codon 12 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 individuals with hereditary breast and ovarian cancer (HBOC). Additionally, this variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variant ID 37929). In summary, the p.Asn1626fs variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP criteria applied: PS4, PM2_Supporting, PVS1.
Color Diagnostics, LLC DBA Color Health	RCV000131079	SCV000683659	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-29	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 4874_4875delAA, 4877delAA, 5102delAA, and 5104delAA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with ovarian cancer (PMID 26681312, 24728189, 22006311, 20609468, 11179017, Color internal data), prostate cancer (PMID: 29915322, 27989354, 24556621, 23524863, 21952622, Color internal data), breast cancer (PMID: 28087643, 28503720, 28008555, 26787237, Color internal data), and an individual affected with pancreatic cancer (Color internal data). This variant has been identified in 2/249578 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	RCV000044510	SCV000694809	pathogenic	Hereditary breast ovarian cancer syndrome	2017-06-27	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.4876_4877delAA (p.Asn1626Serfs) variant (alternatively also known as 5102delAA) 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. p.Val1814X, p.Lys1872X, p.Cys1885X, etc.). This variant is absent in 122720 control chromosomes (including ExAC). This variant has been reported in several HBOC patients in literature and clinical databases. It has also been reported in patients with prostate cancer (Kote-Jarai_2011). In addition, several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000160293	SCV001450051	pathogenic	not provided	2019-04-25	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000160293	SCV002016853	pathogenic	not provided	2022-05-05	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131079	SCV002533909	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-05	criteria provided, single submitter	curation
Baylor Genetics	RCV003147302	SCV003835989	pathogenic	Familial cancer of breast	2024-03-17	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000160293	SCV004226554	pathogenic	not provided	2023-01-12	criteria provided, single submitter	clinical testing	PP5, PM2, PVS1
All of Us Research Program, National Institutes of Health	RCV004803036	SCV004845744	pathogenic	BRCA2-related cancer predisposition	2024-09-18	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 4874_4875delAA, 4877delAA, 5102delAA, and 5104delAA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in 7 individuals affected with ovarian cancer (PMID 26681312, 24728189, 22006311, 20609468, 11179017, Color internal data), 7 individuals affected with prostate cancer (PMID: 29915322, 27989354, 24556621, 23524863, 21952622, Color internal data), 5 individuals affected with breast cancer (PMID: 28087643, 28503720, 28008555, 26787237, Color internal data), and 1 individual affected with pancreatic cancer (Color internal data). In a large breast cancer case-control study, this variant was observed in 1/60466 cases and 1/53461 controls (Leiden Open Variation Database DB-ID BRCA2_003713 PMID: 33471991). This variant has been identified in 2/249578 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.
Sharing Clinical Reports Project (SCRP)	RCV000031510	SCV000054115	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-06-04	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031510	SCV000146498	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044510	SCV000587729	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
GenomeConnect, ClinGen	RCV000044510	SCV000840192	not provided	Hereditary breast ovarian cancer syndrome		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
BRCAlab, Lund University	RCV000031510	SCV004243643	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing