Submissions for variant NM_000059.4(BRCA2):c.3751dup (p.Thr1251fs)

dbSNP: rs397507683

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000241325	SCV000300661	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.
GeneDx	RCV000497278	SCV000210738	pathogenic	not provided	2022-11-22	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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 3979dupA and 3976insA; This variant is associated with the following publications: (PMID: 12100744, 34637943, 29922827, 33754277, 12112655, 17826769, 25418591, 26187060, 12442265, 27165220, 29339979, 30720243, 30014164, 30489631, 21156238, 29446198, 32658311, 34426522, 31851867, 35418818, 33629534, 35216584, Gezdirici_2021)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000241325	SCV000326910	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000241325	SCV000605631	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-07-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000569057	SCV000673102	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-23	criteria provided, single submitter	clinical testing	The c.3751dupA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of A at nucleotide position 3751, causing a translational frameshift with a predicted alternate stop codon (p.T1251Nfs*14). This alteration was identified in a Turkish patient with ovarian cancer as well as an Iranian patient with early onset breast cancer (Yazici H et al. Hum. Mutat., 2002 Jul;20:28-34; Kwong A et al. J. Med. Genet., 2016 Jan;53:15-23). Of note, this alteration is also designated as 3976insA and 3979insA 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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000241325	SCV000746288	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-12-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779989	SCV000916971	pathogenic	Hereditary breast ovarian cancer syndrome	2022-12-19	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3751dupA (p.Thr1251AsnfsX14) 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 245816 control chromosomes (gnomAD). The variant, c.3751dupA, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (examples: Heramb_2018, Yassaee_2002, Yazici_2002). 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. Twelve ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000569057	SCV000996187	pathogenic	Hereditary cancer-predisposing syndrome	2018-08-15	criteria provided, single submitter	clinical testing	This frameshifting variant in exon 11 of 28 introduces a premature stop codon and is predicted to result in loss of normal protein function. This variant has been previously reported as a disease-causing variant in the literature (PMID: 29339979 , 26187060, 12112655, 27165220). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004% (1/240830) and thus is presumed to be rare. Based on the available evidence, the c.3751dupA (p.Thr1251AsnfsTer14) is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000569057	SCV001353292	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-16	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 3976insA or 3979insA in the nomenclature. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least two individuals affected with breast or ovarian cancer (PMID: 12100744, 12112655, 33471991; Leiden Open Variation Database DB-ID BRCA2_001195) and a suspected hereditary breast and ovarian cancer family (PMID: 29339979). This variant has been identified in 1/245816 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.
CeGaT Center for Human Genetics Tuebingen	RCV000497278	SCV001501468	pathogenic	not provided	2021-04-01	criteria provided, single submitter	clinical testing
Invitae	RCV000779989	SCV001591274	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr1251Asnfs*14) 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 (rs397507683, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 12112655, 17826769, 27165220). This variant is also known as c.3976insA and c.3979insA. ClinVar contains an entry for this variant (Variation ID: 51516). For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center	RCV000241325	SCV002580804	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-03-14	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000497278	SCV003813817	pathogenic	not provided	2022-04-04	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000497278	SCV004027421	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473331	SCV004210406	pathogenic	Familial cancer of breast	2023-01-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000779989	SCV004848793	pathogenic	Hereditary breast ovarian cancer syndrome	2022-11-03	criteria provided, single submitter	clinical testing	The p.Thr1251AsnfsX14 variant in BRCA2 has been reported in at least 3 individuals affected with breast cancer and segregated with disease in 1 affected family member (Yassaee 2002 PMID: 12100744, Yazici 2002 PMID: 12112655, Kwong 2015 PMID: 26187060, Heramb 2018 PMID: 29339979). This variant was classified as Pathogenic on September 8, 2016 by the ClinGen-approved Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (Variation ID 51516) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1251 and leads to a premature termination codon 14 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer (HBOC) syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PM2_Supporting, PVS1, PS4_Supporting.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000241325	SCV005046000	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-05-27	criteria provided, single submitter	clinical testing	PVS1; PM5_PTC_Strong
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001568366	SCV001792251	pathogenic	Breast carcinoma	2021-08-18	no assertion criteria provided	clinical testing	Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Positive
BRCAlab, Lund University	RCV000241325	SCV002588867	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing