NM_000059.4(BRCA2):c.4090A>G (p.Ile1364Val) AND Breast-ovarian cancer, familial, susceptibility to, 2

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 30, 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:: RCV000410854.4

Allele description [Variation Report for NM_000059.4(BRCA2):c.4090A>G (p.Ile1364Val)]

NM_000059.4(BRCA2):c.4090A>G (p.Ile1364Val)

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.4090A>G (p.Ile1364Val)

HGVS:

NC_000013.11:g.32338445A>G
NG_012772.3:g.27966A>G
NM_000059.4:c.4090A>GMANE SELECT
NP_000050.2:p.Ile1364Val
NP_000050.3:p.Ile1364Val
LRG_293t1:c.4090A>G
LRG_293:g.27966A>G
LRG_293p1:p.Ile1364Val
NC_000013.10:g.32912582A>G
NM_000059.3:c.4090A>G
p.I1364V

Protein change:

I1364V

Links:

dbSNP: rs56248502

NCBI 1000 Genomes Browser:

rs56248502

Molecular consequence:

NM_000059.4:c.4090A>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
SCV000489410	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Oct 3, 2016)	unknown	clinical testing	Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV004845270	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Nov 30, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32894085, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000489410

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Dominant Disease Classification criteria (2015))

Uncertain significance
(Oct 3, 2016)

unknown

clinical testing

Counsyl Autosomal Dominant Disease Classification criteria (2015),

Citation Link,

SCV004845270

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Nov 30, 2023)

germline

clinical testing

PubMed (2)
[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	2	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

Citations

PubMed

Contribution of BRCA1 and BRCA2 germline mutations to early onset breast cancer: a series from north of Morocco.

Bakkach J, Mansouri M, Derkaoui T, Loudiyi A, El Fahime E, Barakat A, Ghailani Nourouti N, Martinez De Villarreal J, Cortijo Bringas C, Bennani Mechita M.

BMC Cancer. 2020 Sep 7;20(1):859. doi: 10.1186/s12885-020-07352-9.

PubMed [citation]

PMID:: 32894085
PMCID:: PMC7487731

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Counsyl, SCV000489410.2

#	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, SCV004845270.1

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

Description

This missense variant replaces isoleucine with valine at codon 1364 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with early-onset breast cancer, who also carried a pathogenic variant in BRCA1 that could explain the observed phenotype (PMID:32894085). This variant has been identified in 4/280752 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		2	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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