NM_000059.4(BRCA2):c.574_575del (p.Met192fs) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Aug 17, 2023
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:: RCV000235138.24

Allele description [Variation Report for NM_000059.4(BRCA2):c.574_575del (p.Met192fs)]

NM_000059.4(BRCA2):c.574_575del (p.Met192fs)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.574_575del (p.Met192fs)

Other names:

802_803delAT

HGVS:

NC_000013.10:g.32900691_32900692del
NC_000013.11:g.32326554AT[1]
NG_012772.3:g.16075AT[1]
NM_000059.4:c.574_575delMANE SELECT
NP_000050.3:p.Met192fs
LRG_293:g.16075AT[1]
NC_000013.10:g.32900691AT[1]
NC_000013.10:g.32900691_32900692del
NC_000013.10:g.32900693_32900694del
NC_000013.10:g.32900693_32900694delAT
NM_000059.3:c.574_575delAT
NM_000059.4:c.574_575del
U43746.1:n.802_803delAT
p.M192Vfs*13
p.M192VfsX13
p.Met192Valfs*13
p.Met192fs

Nucleotide change:

802delAT

Protein change:

M192fs

Links:

Breast Cancer Information Core (BIC) (BRCA2): 802&base_change=del AT; dbSNP: rs80359533

NCBI 1000 Genomes Browser:

rs80359533

Molecular consequence:

NM_000059.4:c.574_575del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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Xenopus laevis hypothetical protein MGC53617, mRNA (cDNA clone MGC:53617 IMAGE:4...
Xenopus laevis hypothetical protein MGC53617, mRNA (cDNA clone MGC:53617 IMAGE:4684252), complete cds
gi|27769189|gb|BC042358.1|

Nucleotide
SRX24389845 (1)
SRA

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000210703	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Aug 17, 2023)	germline	clinical testing	Citation Link,
SCV000296730	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Sep 10, 2020)	unknown	clinical testing	PubMed (8) [See all records that cite these PMIDs] 21913181, 23983145, 17899372, 20215541, 12960223, 31090900, 26467025, 26295337
SCV002049627	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Mar 6, 2023)	germline	clinical testing	Citation Link,
SCV004225731	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 4, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	2	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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Earlier age of onset of BRCA mutation-related cancers in subsequent generations.

Litton JK, Ready K, Chen H, Gutierrez-Barrera A, Etzel CJ, Meric-Bernstam F, Gonzalez-Angulo AM, Le-Petross H, Lu K, Hortobagyi GN, Arun BK.

Cancer. 2012 Jan 15;118(2):321-5. doi: 10.1002/cncr.26284. Epub 2011 Sep 12. Erratum in: Cancer. 2012 Jun 1;118(11):2997.

PubMed [citation]

PMID:: 21913181
PMCID:: PMC4369377

Functional analysis of a large set of BRCA2 exon 7 variants highlights the predictive value of hexamer scores in detecting alterations of exonic splicing regulatory elements.

Di Giacomo D, Gaildrat P, Abuli A, Abdat J, Frébourg T, Tosi M, Martins A.

Hum Mutat. 2013 Nov;34(11):1547-57. doi: 10.1002/humu.22428. Epub 2013 Sep 18.

PubMed [citation]

PMID:: 23983145

See all PubMed Citations (9)

Details of each submission

From GeneDx, SCV000210703.17

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

Description

Published functional studies demonstrate a damaging effect: failed to rescue susceptibility to DNA damaging agents (Stauffer et al., 2020); 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 in large population cohorts (gnomAD); Also known as 802delAT and 800delAT, 802_803delAT; This variant is associated with the following publications: (PMID: 12960223, 23983145, 20215541, 16644204, 24131973, 17899372, 26295337, 24094589, 21913181, 31090900, 26681312, 12672316, 30267352, 33758026, 28888541, 30787465, 32393813)

#	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, SCV000296730.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 12960223 (2003), 21913181 (2012), 31090900 (2019)). 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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002049627.3

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

Description

The BRCA2 c.574_575delAT; p.Met192ValfsTer13 variant (rs80359533), also known as 800delAT and 802_803delAT, has been described in the literature in individuals and families with breast and ovarian cancer (Evans 2003, Susswein 2016). The variant is listed in the ClinVar database (Variation ID: 37993) but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting 2 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: Evans DG et al. Sensitivity of BRCA1/2 mutation testing in 466 breast/ovarian cancer families. J Med Genet. 2003 Sep;40(9):e107. PMID: 12960223. Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32. PMID: 26681312.

#	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 Mayo Clinic Laboratories, Mayo Clinic, SCV004225731.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (1)

Description

PP5, PM2, PVS1

#	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		2	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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