NM_000059.4(BRCA2):c.229A>G (p.Thr77Ala) AND Breast-ovarian cancer, familial, susceptibility to, 2

Germline classification:: Uncertain significance (5 submissions)
Last evaluated:: Oct 6, 2023
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:: RCV000031361.8

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]

Observations:

Condition(s)

Name:: Breast-ovarian cancer, familial, susceptibility to, 2 (BROVCA2)
Synonyms:: Breast-ovarian cancer, familial 2
Identifiers:: MONDO: MONDO:0012933; MedGen: C2675520; Orphanet: 145; OMIM: 612555

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000053966	Sharing Clinical Reports Project (SCRP)	no assertion criteria provided	Uncertain significance (Apr 12, 2012)	germline	clinical testing
SCV000146412	Breast Cancer Information Core (BIC) (BRCA2)	no assertion criteria provided	Uncertain significance (Feb 20, 2004)	germline	clinical testing
SCV000785960	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Jan 22, 2018)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 24448238, 24835992, 18284688, 26317927 Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf, Citation Link,
SCV001138948	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV004846747	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Oct 6, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18284688, 33606809, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
African	germline	yes	4	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

BRCA2 phosphorylated by PLK1 moves to the midbody to regulate cytokinesis mediated by nonmuscle myosin IIC.

Takaoka M, Saito H, Takenaka K, Miki Y, Nakanishi A.

Cancer Res. 2014 Mar 1;74(5):1518-28. doi: 10.1158/0008-5472.CAN-13-0504. Epub 2014 Jan 21.

PubMed [citation]

PMID:: 24448238

BRCA2 coordinates the activities of cell-cycle kinases to promote genome stability.

Yata K, Bleuyard JY, Nakato R, Ralf C, Katou Y, Schwab RA, Niedzwiedz W, Shirahige K, Esashi F.

Cell Rep. 2014 Jun 12;7(5):1547-1559. doi: 10.1016/j.celrep.2014.04.023. Epub 2014 May 15.

PubMed [citation]

PMID:: 24835992
PMCID:: PMC4062933

See all PubMed Citations (6)

Details of each submission

From Sharing Clinical Reports Project (SCRP), SCV000053966.3

#	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	not provided	1	not provided	not provided		not provided	not provided	not provided	not provided

From Breast Cancer Information Core (BIC) (BRCA2), SCV000146412.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	African	4	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	yes	not provided	not provided	not provided		4	not provided	not provided	not provided

From Counsyl, SCV000785960.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

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

From Mendelics, SCV001138948.1

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

From All of Us Research Program, National Institutes of Health, SCV004846747.1

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

Description

This missense variant replaces threonine with alanine at codon 77 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant disrupts BRCA2-PLK1 interaction. This variant has been reported in 2 individuals affected with breast cancer (PMID: 18284688, 33606809). This variant has been identified in 3/251384 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Jun 2, 2024

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