Submissions for variant NM_000059.4(BRCA2):c.5621_5624del (p.Ile1874fs)

dbSNP: rs80359526

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031561	SCV000300907	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000416547	SCV000072711	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile1874Argfs*34) 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 (rs80359526, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 9042907, 10449599, 18042939, 19620486, 21913181, 26681312). This variant is also known as 5849del4. ClinVar contains an entry for this variant (Variation ID: 37980). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131115	SCV000186045	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-07	criteria provided, single submitter	clinical testing	The c.5621_5624delTTAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 5621 to 5624, causing a translational frameshift with a predicted alternate stop codon (p.I1874Rfs*34). This alteration has been identified in multiple individuals with Hereditary Breast and Ovarian Cancer (HBOC) syndrome (Serova OM et al. Am. J. Hum. Genet. 1997 Mar;60:486-95; Santarosa M et al. Int. J. Cancer. 1999 Sep;83:5-9; Bonadona V et al. Genes Chromosomes Cancer 2005 Aug;43:404-13; Litton JK et al. Cancer. 2012 Jan;118:321-5). Of note, this alteration is also designated as 5849del4-ter1907 and 5849del4 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	RCV000223208	SCV000278863	pathogenic	not provided	2023-12-04	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 individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 9042907, 15887246, 16528604, 18042939, 19620486, 21913181, 28503720, 29907814, 29566657, 30736435); 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 5849_5852delTTAA or 5849del4; This variant is associated with the following publications: (PMID: 15887246, 19620486, 9042907, 26681312, 18042939, 16170354, 21913181, 15131399, 16528604, 28503720, 29566657, 29907814, 29161300, 30720243, 30736435, 30787465, 29922827, 36367610)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000031561	SCV000296575	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-01-25	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031561	SCV000327247	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000416547	SCV000494294	pathogenic	Hereditary breast ovarian cancer syndrome	2023-02-06	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5621_5624delTTAA (p.Ile1874ArgfsX34) 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 247614 control chromosomes.The variant, c.5621_5624delTTAA, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Serova_1997, Santarosa_1999, Tai_2007, Watson_2009, Litton_2011, Alemar_2017, Palmer_2020, Wang_2018 etc.). 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. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000131115	SCV000683716	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	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 identified in 1/247614 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.
Revvity Omics, Revvity	RCV000223208	SCV002019175	pathogenic	not provided	2019-06-11	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000223208	SCV004027442	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460517	SCV004216056	pathogenic	Familial cancer of breast	2024-01-02	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031561	SCV000054166	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2010-06-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031561	SCV000146647	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	RCV000416547	SCV000587782	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353399	SCV000591978	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Ile1874ArgfsX34 deletion variant has been reported in the literature 1 of 62 proband chromosomes in a family with hereditary breast cancer (Serova_1997_9042907). This variant was also identified 3 times in the UMD database as a causal variant and 16 times in the BIC database as having clinical importance. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1874 and leads to a premature stop codon 34 codons downstream. 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 families and is the type of variant that is expected to cause the disorder. In summary, based on the above information, this variant is classified as pathogenic.
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001579294	SCV001805827	pathogenic	Breast carcinoma	2021-08-21	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031561	SCV002588890	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing