NM_000059.4(BRCA2):c.581G>A (p.Trp194Ter) AND not provided

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Dec 3, 2021
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:: RCV000656583.23

Allele description [Variation Report for NM_000059.4(BRCA2):c.581G>A (p.Trp194Ter)]

NM_000059.4(BRCA2):c.581G>A (p.Trp194Ter)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.581G>A (p.Trp194Ter)

HGVS:

NC_000013.11:g.32326563G>A
NG_012772.3:g.16084G>A
NM_000059.4:c.581G>AMANE SELECT
NP_000050.2:p.Trp194Ter
NP_000050.3:p.Trp194Ter
LRG_293t1:c.581G>A
LRG_293:g.16084G>A
LRG_293p1:p.Trp194Ter
NC_000013.10:g.32900700G>A
NM_000059.3:c.581G>A
U43746.1:n.809G>A
p.Trp194*

Nucleotide change:

809G>A

Protein change:

W194*

Links:

dbSNP: rs80358809

NCBI 1000 Genomes Browser:

rs80358809

Molecular consequence:

NM_000059.4:c.581G>A - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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Meconopsis torquata chloroplast, complete genome
Meconopsis torquata chloroplast, complete genome
gi|2651584233|gb|PP112995.1|

Nucleotide
adhesion G protein-coupled receptor L2 isoform 6 precursor [Homo sapiens]
adhesion G protein-coupled receptor L2 isoform 6 precursor [Homo sapiens]
gi|1184495159|ref|NP_001337628.1|

Protein
LOC115931062 [Gorilla gorilla gorilla]
LOC115931062 [Gorilla gorilla gorilla]
Gene ID:115931062

Gene
KIAA0232 [Callithrix jacchus]
KIAA0232 [Callithrix jacchus]
Gene ID:100389146

Gene
Tm4sf1 transmembrane 4 L six family member 1 [Rattus norvegicus]
Tm4sf1 transmembrane 4 L six family member 1 [Rattus norvegicus]
Gene ID:295061

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000778634	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 24, 2019)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 25525159, 25652403, 23983145, 26577449, 8673091, 25741868
SCV000858443	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Dec 6, 2017)	germline	clinical testing	Citation Link,
SCV001801816	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Nov 16, 2021)	germline	clinical testing	Citation Link,
SCV002016909	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 3, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002069049	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 3, 2018)	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	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.

Xiong HY, Alipanahi B, Lee LJ, Bretschneider H, Merico D, Yuen RK, Hua Y, Gueroussov S, Najafabadi HS, Hughes TR, Morris Q, Barash Y, Krainer AR, Jojic N, Scherer SW, Blencowe BJ, Frey BJ.

Science. 2015 Jan 9;347(6218):1254806. doi: 10.1126/science.1254806. Epub 2014 Dec 18.

PubMed [citation]

PMID:: 25525159
PMCID:: PMC4362528

Functional variant analyses (FVAs) predict pathogenicity in the BRCA1 DNA double-strand break repair pathway.

Loke J, Pearlman A, Upadhyay K, Tesfa L, Shao Y, Ostrer H.

Hum Mol Genet. 2015 Jun 1;24(11):3030-7. doi: 10.1093/hmg/ddv048. Epub 2015 Feb 4.

PubMed [citation]

PMID:: 25652403

See all PubMed Citations (6)

Details of each submission

From Mayo Clinic Laboratories, Mayo Clinic, SCV000778634.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (6)

Description

PVS1, PS3, PM2, PP5

#	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		1	not provided	not provided	not provided

From Eurofins Ntd Llc (ga), SCV000858443.1

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

From GeneDx, SCV001801816.3

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

Description

Nonsense 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 occasional alternate splicing resulting in both the pathogenic deletion of exon 7 or the in-frame naturally occurring deletion of exons 4-7 which may result in a functional protein (Biswas 2011, Di Giacomo 2013, Mesman 2020); Observed in multiple individuals with Hereditary Breast and Ovarian Cancer (Couch 1996, Shih 2002, Francies 2015, Yang 2017, Chan 2018); Not observed at significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 809G>A; This variant is associated with the following publications: (PMID: 22962691, 26920070, 23983145, 8673091, 21719596, 25652403, 11844822, 28664506, 28301456, 26577449, 30093976, 29843852, 29446198, 32398771, 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 Revvity Omics, Revvity, SCV002016909.3

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV002069049.1

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

Description

DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.581G>A, which results in the creation of a premature stop codon at amino acid position 194, p.Trp194*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated BRCA2 protein with potentially abnormal function. In vitro assays have provided evidence that the p.Trp194* sequence change leads to skipping of exon 7, altered protein nuclear localization and reduced p53 phosphorylation (Loke et al., 2015. Hum Mol Genet 24: 3030-7; Di Giacomo et al., 2013. Hum Mutat 34: 1547-57). This pathogenic sequence change has previously been described in a patient with BRCA2-related breast cancer (PMID: 8673091).

#	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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