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NM_000059.4(BRCA2):c.4165T>G (p.Phe1389Val) AND Breast-ovarian cancer, familial, susceptibility to, 2

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
May 4, 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:
RCV003447540.4

Allele description [Variation Report for NM_000059.4(BRCA2):c.4165T>G (p.Phe1389Val)]

NM_000059.4(BRCA2):c.4165T>G (p.Phe1389Val)

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.4165T>G (p.Phe1389Val)
HGVS:
  • NC_000013.11:g.32338520T>G
  • NG_012772.3:g.28041T>G
  • NM_000059.4:c.4165T>GMANE SELECT
  • NP_000050.2:p.Phe1389Val
  • NP_000050.3:p.Phe1389Val
  • LRG_293t1:c.4165T>G
  • LRG_293:g.28041T>G
  • LRG_293p1:p.Phe1389Val
  • NC_000013.10:g.32912657T>G
  • NM_000059.3:c.4165T>G
Protein change:
F1389V
Links:
dbSNP: rs1409088355
NCBI 1000 Genomes Browser:
rs1409088355
Molecular consequence:
  • NM_000059.4:c.4165T>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
2

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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004175796Neuberg Centre For Genomic Medicine, NCGM
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Feb 14, 2023) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004845278All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(May 4, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknown2not providednot provided108544not providedclinical testing

Citations

PubMed

Screening of over 1000 Indian patients with breast and/or ovarian cancer with a multi-gene panel: prevalence of BRCA1/2 and non-BRCA mutations.

Singh J, Thota N, Singh S, Padhi S, Mohan P, Deshwal S, Sur S, Ghosh M, Agarwal A, Sarin R, Ahmed R, Almel S, Chakraborti B, Raina V, DadiReddy PK, Smruti BK, Rajappa S, Dodagoudar C, Aggarwal S, Singhal M, Joshi A, Kumar R, et al.

Breast Cancer Res Treat. 2018 Jul;170(1):189-196. doi: 10.1007/s10549-018-4726-x. Epub 2018 Feb 22.

PubMed [citation]
PMID:
29470806

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 Neuberg Centre For Genomic Medicine, NCGM, SCV004175796.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

The missense c.4165T>G(p.Phe1389Val) variant in BRCA2 gene has been reported previously in individual affected with BRCA2associated disorders (Reeba Mary Issac, et. al., 2022). The variant is reported with an allele frequency of 0.0004% in the gnomADexomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVardatabase as Uncertain significance (multiple submission). The amino acid change p.Phe1389Val in BRCA2 is predicted asconserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Phe at position 1389 is changed to a Val changing proteinsequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classifiedas Variant of Uncertain Significance (VUS).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From All of Us Research Program, National Institutes of Health, SCV004845278.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (2)

Description

This missense variant replaces phenylalanine with valine at codon 1389 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 three individuals affected with breast or ovarian cancer (PMID: 29470806, DOI: 10.4103/bbrj.bbrj_206_21). This variant has been identified in 1/237332 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided2not providednot providednot provided

Last Updated: Oct 26, 2024