Submissions for variant NM_000059.4(BRCA2):c.4258del (p.Asp1420fs)

gnomAD frequency: 0.00001  dbSNP: rs80359436

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077322	SCV000300729	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	RCV000165445	SCV000216175	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-13	criteria provided, single submitter	clinical testing	The c.4258delG pathogenic mutation is located in coding exon 10 of the BRCA2 gene. This results from a deletion of one nucleotide at nucleotide position 4258, causing a translational frameshift with a predicted alternate stop codon (p.D1420Ifs*28). This mutation has been reported in two unrelated Scandinavian families with histories of breast, cervical, and pancreatic cancers, as well as in tumor tissue from three unrelated males diagnosed with breast cancer (Håkansson S et al. Am J Hum Genet. 1997 May;60(5):1068-78). The c.4258delG pathogenic mutation is commonly found in the Swedish population and has been reported as a Swedish founder mutation (Janaviius R. EPMA J. 2010 Sep;1(3):397-412). Of note, this mutation is also designated as 4486delG. 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.
Counsyl	RCV000077322	SCV000220817	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-20	criteria provided, single submitter	literature only
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077322	SCV000326996	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000077322	SCV000605650	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-07-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000657225	SCV000778951	pathogenic	not provided	2017-07-05	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in BRCA2 is denoted c.4258delG at the cDNA level and p.Asp1420IlefsX28 (D1420IfsX28) at the protein level. The normal sequence, with the base that is deleted in brackets, is TAAAA[delG]ATTT. The deletion causes a frameshift which changes an Aspartic Acid to an Isoleucine at codon 1420, and creates a premature stop codon at position 28 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.4258delG has been observed in association with breast cancer and is known to be a pathogenic founder variant in the Swedish population (Hakansson 1997, Haraldsson 1998, Loman 2001, Janavicius 2010). We consider this variant to be pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000999883	SCV000883495	pathogenic	not specified	2018-08-06	criteria provided, single submitter	clinical testing	The BRCA2 c.4258delG; p.Asp1420fs variant (rs80359436), also known as 4486delG, is reported in the literature in families with breast cancer (Hakansson 1997, Winter 2016), and is commonly found in the Swedish population (Janavicius 2010). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 51617), and is observed in the general population with a low overall allele frequency of 0.0008% (2/240284 alleles) in the Genome Aggregation Database. This variant deletes a single nucleotide causing a frameshift, and is predicted to result in a truncated protein or absent transcript. Based on the above information, this variant is considered pathogenic. REFERENCES Hakansson S et al. Moderate frequency of BRCA1 and BRCA2 germ-line mutations in Scandinavian familial breast cancer. Am J Hum Genet. 1997 May;60(5):1068-78. Janavicius R. Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control. EPMA J. 2010 Sep;1(3):397-412. Winter C et al. Targeted sequencing of BRCA1 and BRCA2 across a large unselected breast cancer cohort suggests that one-third of mutations are somatic. Ann Oncol. 2016 Aug;27(8):1532-8.
Color Diagnostics, LLC DBA Color Health	RCV000165445	SCV000906907	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-09	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide 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 is a known Swedish founder mutation and has been reported in 5 individuals affected with breast cancer, including 3 male individuals, and has also been observed in unaffected individuals (PMID: 10615237, 11504767, 33471991). This variant has been identified in 19 families among the CIMBA participants (PMID: 29446198). This variant has been identified in 2/244196 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496923	SCV001585418	pathogenic	Hereditary breast ovarian cancer syndrome	2022-06-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp1420Ilefs*28) 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 (rs80359436, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 9150154). This variant is also known as c.4486delG. ClinVar contains an entry for this variant (Variation ID: 51617). For these reasons, this variant has been classified as Pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000657225	SCV004027423	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000657225	SCV005199787	pathogenic	not provided	2023-09-18	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077322	SCV000109119	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-04-17	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077322	SCV000146396	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	RCV000496923	SCV000587706	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
BRCAlab, Lund University	RCV000077322	SCV002588874	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing