Submissions for variant NM_000059.4(BRCA2):c.3744_3747del (p.Ser1248fs)

dbSNP: rs80359403

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)	RCV000031437	SCV000282382	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	RCV000044254	SCV000072267	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser1248Argfs*10) 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 (rs80359403, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast/ovarian cancer (PMID: 11802209, 16455195, 18489799, 19656164, 26187060). This variant is also known as 3972del4. ClinVar contains an entry for this variant (Variation ID: 37856). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131096	SCV000186026	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-14	criteria provided, single submitter	clinical testing	The c.3744_3747delTGAG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 3744 to 3747, causing a translational frameshift with a predicted alternate stop codon (p.S1248Rfs*10). This alteration has been reported in multiple breast and/or ovarian cancer families (Foretova L et al. Hum. Mutat. 2004 Apr;23:397-8; Li WF et al. Breast Cancer Res. Treat. 2008 Jul;110:99-109; Jang JH et al. J. Hum. Genet. 2012 Mar;57:212-5; Song WH et al. J. Korean Med. Sci. 2017 Feb;32:377-381; Park B et al. Breast Cancer Res. Treat. 2017 May;163:139-150; Concolino P et al. Int J Mol Sci, 2019 Jul;20:; Bang YJ et al. Cancer Res Treat, 2021 Oct;:). Of note, this alteration is also designated as 3972_3975delTGAG and 3972del4 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485903	SCV000296741	pathogenic	not provided	2020-11-12	criteria provided, single submitter	clinical testing	This variant has been reported in individuals affected with breast cancer, prostate cancer, and ovarian cancer in the published literature (PMID: 28724667 (2017), 28205045 (2017), 28049253 (2017), 26306726 (2015), 26187060 (2015), 25863477 (2015), 22798144 (2012)). 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	RCV000031437	SCV000326909	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000485903	SCV000568466	pathogenic	not provided	2020-06-30	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; Observed in several individuals with personal and family history of Hereditary Breast and Ovarian Cancer syndrome and is a recurrent variant in the Korean population (Kang 2002, Meindl 2002, Kim 2012, Minucci 2015, Kwong 2016, Song 2017); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek 2016); Also known as 3972_3975delTGAG and 3972del4; This variant is associated with the following publications: (PMID: 25007954, 28724667, 26295337, 11802209, 19499246, 19656164, 12204006, 17100994, 16455195, 18489799, 17851763, 22798144, 22217648, 22382806, 24155753, 26187060, 28049253, 26709275, 26306726, 28392550, 28205045, 29673794, 28111427, 30720243, 30702160, 28726808, 31214711)
Color Diagnostics, LLC DBA Color Health	RCV000131096	SCV000683579	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-25	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 11 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 observed in over twenty individuals affected with breast cancer and is known to be a recurrent disease-causing mutation in the Korean population (PMID: 25863477, 26187060, 28205045, 34063308). This variant has been identified in 1/246600 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	RCV000044254	SCV000694716	pathogenic	Hereditary breast ovarian cancer syndrome	2022-07-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3744_3747delTGAG (p.Ser1248ArgfsX10) 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 4.1e-06 in 246600 control chromosomes (gnomAD). c.3744_3747delTGAG has been reported in the literature in multiple individuals affected with Hereditary Breast And/or Ovarian Cancer (examples: Kang_2015, Minucci_2015 and Song_2017). These data indicate that the variant is very likely to be associated with disease. Thirteen submitters including an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics	RCV000044254	SCV000838788	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002405	SCV001160335	pathogenic	not specified	2019-02-14	criteria provided, single submitter	clinical testing	The BRCA2 c.3744_3747delTGAG; p.Ser1248fs variant (rs80359403) is reported in the literature in numerous individuals with a personal or family history of breast and/or ovarian cancer (Machackova 2008, Meindl 2002, Park 2016, Park 2017, Seong 2009). This variant is found on a single chromosome in the Genome Aggregation Database, indicating it is not a common polymorphism, and it is reported as pathogenic by numerous laboratories in ClinVar (Variation ID: 37856). This variant causes a frameshift by deleting 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: Machackova E et al. Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer. BMC Cancer. 2008 May 20;8:140. Meindl A et al. Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population. Int J Cancer. 2002 Feb 1;97(4):472-80. Park B et al. Characteristics of BRCA1/2 mutations carriers including large genomic rearrangements in high risk breast cancer patients. Breast Cancer Res Treat. 2017 May;163(1):139-150. Park J et al. Comparison of Targeted Next-Generation and Sanger Sequencing for the BRCA1 and BRCA2 Mutation Screening. Ann Lab Med. 2016 Mar;36(2):197-201. Seong MW et al. Comprehensive mutational analysis of BRCA1/BRCA2 for Korean breast cancer patients: evidence of a founder mutation. Clin Genet. 2009 Aug;76(2):152-60.
Division of Medical Genetics, University of Washington	RCV000031437	SCV001434320	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-07	criteria provided, single submitter	clinical testing	This variant leads to a translational frameshift and the introduction of a premature termination codon at position 10 of the new reading frame. The variant transcript is predicted to be unstable and degraded by nonsense-mediated decay. Loss of expression of one allele of BRCA2 is a well-established mechanism of disease for Hereditary Breast and Ovarian cancer (Borg 2010). This variant has been reported in the literature in multiple individuals and families with breast and/or ovarian cancer (Meindl 2001, Ahn 2007, Machackova 2008, Seong 2009, Kwong 2016). This variant has an allele frequency of 0.000004 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). Thus, this variant is interpreted as pathogenic. PS4-moderate; PVS1
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000485903	SCV001449721	pathogenic	not provided	2018-04-03	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310146	SCV001499724	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000485903	SCV002497655	pathogenic	not provided	2022-03-01	criteria provided, single submitter	clinical testing	BRCA2: PVS1, PM2, PS4:Moderate
MGZ Medical Genetics Center	RCV000031437	SCV002579645	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-11-12	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496480	SCV002811040	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2021-10-20	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000485903	SCV003810456	pathogenic	not provided	2022-09-21	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460507	SCV004213592	pathogenic	Familial cancer of breast	2023-09-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031437	SCV004845213	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-03-23	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 11 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 observed in over twenty individuals affected with breast cancer and is known to be a recurrent disease-causing mutation in the Korean population (PMID: 25863477, 26187060, 28205045, 34063308). This variant has been identified in 1/246600 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)	RCV000031437	SCV000054042	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2010-02-26	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031437	SCV000146289	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	RCV000044254	SCV000587680	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
BRCAlab, Lund University	RCV000031437	SCV002588865	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing