NM_000059.4(BRCA2):c.771_775del (p.Asn257fs) AND not provided

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Jul 31, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000212208.28

Allele description [Variation Report for NM_000059.4(BRCA2):c.771_775del (p.Asn257fs)]

NM_000059.4(BRCA2):c.771_775del (p.Asn257fs)

Gene:

BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.771_775del (p.Asn257fs)

Other names:

995del5

HGVS:

NC_000013.10:g.32905141_32905145del
NC_000013.11:g.32331008_32331012del
NG_012772.3:g.20529_20533del
NM_000059.4:c.771_775delMANE SELECT
NP_000050.3:p.Asn257fs
LRG_293:g.20529_20533del
NC_000013.10:g.32905141_32905145del
NC_000013.10:g.32905145_32905149del
NC_000013.10:g.32905145_32905149del
NC_000013.10:g.32905145_32905149delTCAAA
NM_000059.3:c.771_775delTCAAA
NM_000059.4:c.771_775delTCAAA
U43746.1:n.995_999delCAAAT
U43746.1:n.999_1003delTCAAA
p.Asn257Lysfs*17
p.N257KFS*17
p.N257KfsX17

Nucleotide change:

999del5

Links:

Breast Cancer Information Core (BIC) (BRCA2): 995&base_change=del CAAAT; Breast Cancer Information Core (BIC) (BRCA2): 999&base_change=del TCAAA; OMIM: 600185.0010; dbSNP: rs80359671

NCBI 1000 Genomes Browser:

rs80359671

Molecular consequence:

NM_000059.4:c.771_775del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Defensin beta 6 [Mus musculus]
Defensin beta 6 [Mus musculus]
gi|111601336|gb|AAI19424.1|

Protein
Naumovozyma dairenensis CBS 421 chromosome 2, complete genome
Naumovozyma dairenensis CBS 421 chromosome 2, complete genome
gi|365984159|ref|NC_016480.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000210707	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Aug 1, 2023)	germline	clinical testing	Citation Link,
SCV000887922	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Sep 29, 2020)	unknown	clinical testing	PubMed (24) [See all records that cite these PMIDs] 15571962, 26689913, 27062684, 28724667, 29339979, 29625052, 29752822, 30350268, 30702160, 30720243, 30787465, 30875412, 31159747, 31825140, 32341426, 9802270, 8589730, 19478387, 23857704, 17591843, 9634522, 31957001, 30093976, 26467025
SCV001449839	Clinical Genetics and Genomics, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 9, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002010326	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 3, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002550262	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 31, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005199574	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 13, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

BRCA2, but not BRCA1, mutations account for familial ovarian cancer in Iceland: a population-based study.

Rafnar T, Benediktsdottir KR, Eldon BJ, Gestsson T, Saemundsson H, Olafsson K, Salvarsdottir A, Steingrimsson E, Thorlacius S.

Eur J Cancer. 2004 Dec;40(18):2788-93.

PubMed [citation]

PMID:: 15571962

Patterns and functional implications of rare germline variants across 12 cancer types.

Lu C, Xie M, Wendl MC, Wang J, McLellan MD, Leiserson MD, Huang KL, Wyczalkowski MA, Jayasinghe R, Banerjee T, Ning J, Tripathi P, Zhang Q, Niu B, Ye K, Schmidt HK, Fulton RS, McMichael JF, Batra P, Kandoth C, Bharadwaj M, Koboldt DC, et al.

Nat Commun. 2015 Dec 22;6:10086. doi: 10.1038/ncomms10086.

PubMed [citation]

PMID:: 26689913
PMCID:: PMC4703835

See all PubMed Citations (25)

Details of each submission

From GeneDx, SCV000210707.17

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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; Published functional studies demonstrate a damaging effect: shown in expression studies to be extremely unstable and to impact cytokinesis (Mikaelsdottir et al., 2004; Jonsdottir et al., 2009); Reported as a founder pathogenic variant in Iceland, accounting for 7-8% of all breast and ovarian cancer in the country (Johannesdottir et al., 1996; Thorlacius et al., 1997; Jonsdottir et al., 2009); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Tavtigian et al., 1996; Thorlacius et al., 1997; Azzollini et al., 2017; Chan et al., 2018; Bhaskaran et al., 2019); 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 999_1003del; This variant is associated with the following publications: (PMID: 28199346, 23857704, 8589730, 19478387, 8706004, 23747895, 9150155, 27537391, 28235830, 27062684, 29339979, 10807692, 30720243, 30702160, 30093976, 31159747, 31957001, 29625052, 26689913, 30787465, 31723001, 30350268, 31825140, 34254208, 32341426, 9802270, 30875412, 15571962, 34645131, 15217494)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000887922.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (24)

Description

This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, the variant has been reported in individuals affected with breast cancer and has been described as a pathogenic founder variant in the Icelandic population (PMIDs: 31957001 (2020), 30093976 (2018), 23857704 (2013), and 17591843 (2007)). The frequency of this variant in the general population, 0.000092 (2/21636 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics and Genomics, Karolinska University Hospital, SCV001449839.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		3	not provided	not provided	not provided

From Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV002010326.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV002550262.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005199574.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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