NM_000059.4(BRCA2):c.572A>G (p.Asp191Gly) AND Hereditary breast ovarian cancer syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 14, 2019
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV004017342.1

Allele description [Variation Report for NM_000059.4(BRCA2):c.572A>G (p.Asp191Gly)]

NM_000059.4(BRCA2):c.572A>G (p.Asp191Gly)

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.572A>G (p.Asp191Gly)

HGVS:

NC_000013.11:g.32326554A>G
NG_012772.3:g.16075A>G
NM_000059.4:c.572A>GMANE SELECT
NP_000050.2:p.Asp191Gly
NP_000050.3:p.Asp191Gly
LRG_293t1:c.572A>G
LRG_293:g.16075A>G
LRG_293p1:p.Asp191Gly
NC_000013.10:g.32900691A>G
NM_000059.3:c.572A>G

Protein change:

D191G

Links:

dbSNP: rs397507798

NCBI 1000 Genomes Browser:

rs397507798

Molecular consequence:

NM_000059.4:c.572A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary breast ovarian cancer syndrome
Synonyms:: Hereditary breast and ovarian cancer syndrome; Hereditary breast and ovarian cancer; Hereditary breast and ovarian cancer syndrome (HBOC); See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0003582; MeSH: D061325; MedGen: C0677776; Orphanet: 145

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004847903	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Oct 14, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22962691, 30883759, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004847903

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Oct 14, 2019)

germline

clinical testing

PubMed (3)
[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

Multiple sequence variants of BRCA2 exon 7 alter splicing regulation.

Gaildrat P, Krieger S, Di Giacomo D, Abdat J, Révillion F, Caputo S, Vaur D, Jamard E, Bohers E, Ledemeney D, Peyrat JP, Houdayer C, Rouleau E, Lidereau R, Frébourg T, Hardouin A, Tosi M, Martins A.

J Med Genet. 2012 Oct;49(10):609-17. doi: 10.1136/jmedgenet-2012-100965. Epub 2012 Sep 7.

PubMed [citation]

PMID:: 22962691

Mis-splicing in breast cancer: identification of pathogenic BRCA2 variants by systematic minigene assays.

Fraile-Bethencourt E, Valenzuela-Palomo A, Díez-Gómez B, Goina E, Acedo A, Buratti E, Velasco EA.

J Pathol. 2019 Aug;248(4):409-420. doi: 10.1002/path.5268. Epub 2019 Apr 23.

PubMed [citation]

PMID:: 30883759

See all PubMed Citations (3)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847903.1

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

Description

The p.Asp191Gly variant in BRCA2 has been reported in 2 individuals with early-onset breast cancer (Gaildrat 2012). It was absent from large population studies. Computational prediction tools and conservation analysis suggest that the p.Asp191Gly variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additionally, in vitro splicing assays provide evidence that this variant leads to a splicing change, resulting in the in-frame deletion of 20 amino acids (Gaildrat 2012, Fraile-Bethencourt 2019); however, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). ACMG/AMP Criteria applied: PM2, PS3_Moderate, PP3, PS4_Supporting.

#	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: Sep 8, 2024

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