NM_000059.4(BRCA2):c.229A>G (p.Thr77Ala) AND Hereditary breast ovarian cancer syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 14, 2023
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:: RCV001318869.6

Allele description [Variation Report for NM_000059.4(BRCA2):c.229A>G (p.Thr77Ala)]

NM_000059.4(BRCA2):c.229A>G (p.Thr77Ala)

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.229A>G (p.Thr77Ala)

HGVS:

NC_000013.11:g.32319238A>G
NG_012772.3:g.8759A>G
NG_017006.2:g.1126T>C
NM_000059.4:c.229A>GMANE SELECT
NP_000050.2:p.Thr77Ala
NP_000050.3:p.Thr77Ala
LRG_293t1:c.229A>G
LRG_293:g.8759A>G
LRG_293p1:p.Thr77Ala
NC_000013.10:g.32893375A>G
NM_000059.3:c.229A>G
U43746.1:n.457A>G

Nucleotide change:

457A>G

Protein change:

T77A

Links:

dbSNP: rs80358500

NCBI 1000 Genomes Browser:

rs80358500

Molecular consequence:

NM_000059.4:c.229A>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
SCV001509588	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 14, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 18284688, 29684080, 34598035, 24448238, 24835992, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001509588

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 14, 2023)

germline

clinical testing

PubMed (6)
[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

Evaluation of unclassified variants in the breast cancer susceptibility genes BRCA1 and BRCA2 using five methods: results from a population-based study of young breast cancer patients.

Lee E, McKean-Cowdin R, Ma H, Chen Z, Van Den Berg D, Henderson BE, Bernstein L, Ursin G.

Breast Cancer Res. 2008;10(1):R19. doi: 10.1186/bcr1865. Epub 2008 Feb 19.

PubMed [citation]

PMID:: 18284688
PMCID:: PMC2374975

Unexpected cancer-predisposition gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations.

Yehia L, Ni Y, Sesock K, Niazi F, Fletcher B, Chen HJL, LaFramboise T, Eng C.

PLoS Genet. 2018 Apr;14(4):e1007352. doi: 10.1371/journal.pgen.1007352.

PubMed [citation]

PMID:: 29684080
PMCID:: PMC5933810

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV001509588.4

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

Description

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 77 of the BRCA2 protein (p.Thr77Ala). This variant is present in population databases (rs80358500, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer or head and neck carcinoma (PMID: 18284688, 29684080, 34598035). ClinVar contains an entry for this variant (Variation ID: 37780). 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%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 24448238, 24835992). 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

Last Updated: Jun 2, 2024

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