NM_000059.4(BRCA2):c.8663G>A (p.Arg2888His) AND Hereditary breast ovarian cancer syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 14, 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:: RCV001852959.7

Allele description [Variation Report for NM_000059.4(BRCA2):c.8663G>A (p.Arg2888His)]

NM_000059.4(BRCA2):c.8663G>A (p.Arg2888His)

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.8663G>A (p.Arg2888His)

Other names:

p.R2888H:CGT>CAT

HGVS:

NC_000013.11:g.32376700G>A
NG_012772.3:g.66221G>A
NM_000059.4:c.8663G>AMANE SELECT
NP_000050.2:p.Arg2888His
NP_000050.3:p.Arg2888His
LRG_293t1:c.8663G>A
LRG_293:g.66221G>A
LRG_293p1:p.Arg2888His
NC_000013.10:g.32950837G>A
NM_000059.3:c.8663G>A
U43746.1:n.8891G>A

Protein change:

R2888H

Links:

dbSNP: rs80359124

NCBI 1000 Genomes Browser:

rs80359124

Molecular consequence:

NM_000059.4:c.8663G>A - 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
SCV002211188	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 4, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27616075, 28492532
SCV005374684	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	criteria provided, single submitter (ClinGen BRCA2 V1.0.0)	Uncertain significance (May 14, 2024)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002211188

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 4, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV005374684

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

criteria provided, single submitter

(ClinGen BRCA2 V1.0.0)

Uncertain significance
(May 14, 2024)

germline

curation

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2.

Kraus C, Hoyer J, Vasileiou G, Wunderle M, Lux MP, Fasching PA, Krumbiegel M, Uebe S, Reuter M, Beckmann MW, Reis A.

Int J Cancer. 2017 Jan 1;140(1):95-102. doi: 10.1002/ijc.30428. Epub 2016 Sep 23.

PubMed [citation]

PMID:: 27616075

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002211188.3

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

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2888 of the BRCA2 protein (p.Arg2888His). This variant is present in population databases (rs80359124, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 27616075). ClinVar contains an entry for this variant (Variation ID: 52651). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne, SCV005374684.1

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

Description

According to the ClinGen ENIGMA BRCA2 v1.0.0 criteria we chose this criterion: BP4 (supporting benign): BayesDel no-AF -0.1726, SpliceAI 0.01

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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