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

Recent activity

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Homo sapiens chromosome 8, clone CTD-2025J6, complete sequence
Homo sapiens chromosome 8, clone CTD-2025J6, complete sequence
gi|22002210|gnl|WIBR|L10960|gb|AC09 6|

Nucleotide
gja9a gap junction protein alpha 9a [Danio rerio]
gja9a gap junction protein alpha 9a [Danio rerio]
Gene ID:573483

Gene
AGENCOURT_77726620 NICHD_XGC_skin_m Xenopus laevis cDNA clone IMAGE:8642549 5', ...
AGENCOURT_77726620 NICHD_XGC_skin_m Xenopus laevis cDNA clone IMAGE:8642549 5', mRNA sequence
gi|95009044|gnl|dbEST|39150950|gb|E 28.1|

Nucleotide
JGI_CABG8668.rev NIH_XGC_tropSto1 Xenopus tropicalis cDNA clone IMAGE:7839778 3'...
JGI_CABG8668.rev NIH_XGC_tropSto1 Xenopus tropicalis cDNA clone IMAGE:7839778 3', mRNA sequence
gi|71522406|gnl|dbEST|30385439|gb|D 16.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000186405	Ambry Genetics	criteria provided, single submitter (Ambry Autosomal Dominant and X-Linked criteria (9/4/14))	Pathogenic (Jul 19, 2013)	germline	clinical testing	Citation Link,
SCV000186907	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jun 28, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12672316, 20215541, 30267352, 31090900 Citation Link,
SCV000683730	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 17, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 12672316, 21913181, 24094589, 24131973, 26681312, 31090900, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000186405

Ambry Genetics

criteria provided, single submitter

(Ambry Autosomal Dominant and X-Linked criteria (9/4/14))

Pathogenic
(Jul 19, 2013)

germline

clinical testing

Citation Link,

SCV000186907

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jun 28, 2021)

germline

clinical testing

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

Citation Link,

SCV000683730

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 17, 2024)

germline

clinical testing

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

Help

Summary from all submissions

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

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

#	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 Ambry Genetics, SCV000186907.4

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

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

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

#	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

Last Updated: Oct 26, 2024

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