NM_000059.4(BRCA2):c.9730G>T (p.Val3244Phe) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 10, 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:: RCV000216607.9

Allele description [Variation Report for NM_000059.4(BRCA2):c.9730G>T (p.Val3244Phe)]

NM_000059.4(BRCA2):c.9730G>T (p.Val3244Phe)

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.9730G>T (p.Val3244Phe)

HGVS:

NC_000013.11:g.32398243G>T
NG_012772.3:g.87764G>T
NM_000059.4:c.9730G>TMANE SELECT
NP_000050.2:p.Val3244Phe
NP_000050.3:p.Val3244Phe
LRG_293t1:c.9730G>T
LRG_293:g.87764G>T
LRG_293p1:p.Val3244Phe
NC_000013.10:g.32972380G>T
NM_000059.3:c.9730G>T

Nucleotide change:

9958G>T

Protein change:

V3244F

Links:

dbSNP: rs11571831

NCBI 1000 Genomes Browser:

rs11571831

Molecular consequence:

NM_000059.4:c.9730G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000276441	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jan 30, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000689223	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 10, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28664449, 36922933, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000276441

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jan 30, 2023)

germline

clinical testing

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

Citation Link,

SCV000689223

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 10, 2023)

germline

clinical testing

PubMed (3)
[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

Analysis of BRCA1/2 mutation spectrum and prevalence in unselected Chinese breast cancer patients by next-generation sequencing.

Li G, Guo X, Tang L, Chen M, Luo X, Peng L, Xu X, Wang S, Xiao Z, Yi W, Dai L, Wang J.

J Cancer Res Clin Oncol. 2017 Oct;143(10):2011-2024. doi: 10.1007/s00432-017-2465-8. Epub 2017 Jun 29.

PubMed [citation]

PMID:: 28664449

Whole-exome Sequencing of Nigerian Prostate Tumors from the Prostate Cancer Transatlantic Consortium (CaPTC) Reveals DNA Repair Genes Associated with African Ancestry.

White JA, Kaninjing ET, Adeniji KA, Jibrin P, Obafunwa JO, Ogo CN, Mohammed F, Popoola A, Fatiregun OA, Oluwole OP, Karanam B, Elhussin I, Ambs S, Tang W, Davis M, Polak P, Campbell MJ, Brignole KR, Rotimi SO, Dean-Colomb W, Odedina FT, Martin DN, et al.

Cancer Res Commun. 2022 Sep;2(9):1005-1016. doi: 10.1158/2767-9764.CRC-22-0136.

PubMed [citation]

PMID:: 36922933
PMCID:: PMC10010347

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000276441.6

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

Description

The p.V3244F variant (also known as c.9730G>T), located in coding exon 26 of the BRCA2 gene, results from a G to T substitution at nucleotide position 9730. The valine at codon 3244 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been reported in 1/313 unselected breast cancer patients from the Chinese Han population (Li G et al. J. Cancer Res. Clin. Oncol., 2017 Oct;143:2011-2024). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000689223.4

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

Description

This missense variant replaces valine with phenylalanine at codon 3244 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 affected with breast cancer (PMID: 28664449) and an individual affected with prostate cancer (PMID: 36922933). This variant has been identified in 3/251200 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 1, 2024

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