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NM_000059.4(BRCA2):c.574_575del (p.Met192fs) AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic (3 submissions)
Last evaluated:
Jan 17, 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:
RCV000131852.18

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]

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000186405Ambry Genetics
criteria provided, single submitter

(Ambry Autosomal Dominant and X-Linked criteria (9/4/14))
Pathogenic
(Jul 19, 2013)
germlineclinical testing

Citation Link,

SCV000186907Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)
Pathogenic
(Jun 28, 2021)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV000683730Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jan 17, 2024)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

A high proportion of DNA variants of BRCA1 and BRCA2 is associated with aberrant splicing in breast/ovarian cancer patients.

Sanz DJ, Acedo A, Infante M, Durán M, Pérez-Cabornero L, Esteban-Cardeñosa E, Lastra E, Pagani F, Miner C, Velasco EA.

Clin Cancer Res. 2010 Mar 15;16(6):1957-67. doi: 10.1158/1078-0432.CCR-09-2564. Epub 2010 Mar 9.

PubMed [citation]
PMID:
20215541

Referral frequency, attrition rate, and outcomes of germline testing in patients with pancreatic adenocarcinoma.

Walker EJ, Carnevale J, Pedley C, Blanco A, Chan S, Collisson EA, Tempero MA, Ko AH.

Fam Cancer. 2019 Apr;18(2):241-251. doi: 10.1007/s10689-018-0106-2.

PubMed [citation]
PMID:
30267352
See all PubMed Citations (9)

Details of each submission

From Ambry Genetics, SCV000186405.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Ambry Genetics, SCV000186907.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

The c.574_575delAT pathogenic mutation, located in coding exon 6 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 574 to 575, causing a translational frameshift with a predicted alternate stop codon (p.M192Vfs*13). This alteration (also designated 800delAT and 802delAT) has been identified in multiple breast, ovarian, and pancreatic cancer patients (Lalloo F et al. Lancet. 2003 Mar;361:1101-2; Evans DG et al. J. Med. Genet. 2003 Sep;40:e107; Sanz DJ et al. Clin Cancer Res. 2010 Mar;16:1957-67; Litton J et al. Cancer. 2012 Jan;118:321-5; Walker EJ et al. Fam Cancer. 2019 04;18:241-251; Nones K et al. Ann Oncol. 2019 07;30:1071-1079). 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Color Diagnostics, LLC DBA Color Health, SCV000683730.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This variant deletes 2 nucleotides in exon 7 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 800delAT in the literature. 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 six individuals affected with breast and/or ovarian cancer (PMID: 12672316, 21913181, 24094589, 24131973, 26681312, 31090900). This variant has not been identified 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 26, 2024