NM_000059.4(BRCA2):c.7040C>A (p.Pro2347Gln) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 31, 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:: RCV000167327.10

Allele description [Variation Report for NM_000059.4(BRCA2):c.7040C>A (p.Pro2347Gln)]

NM_000059.4(BRCA2):c.7040C>A (p.Pro2347Gln)

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.7040C>A (p.Pro2347Gln)

HGVS:

NC_000013.11:g.32354893C>A
NG_012772.3:g.44414C>A
NM_000059.4:c.7040C>AMANE SELECT
NP_000050.2:p.Pro2347Gln
NP_000050.3:p.Pro2347Gln
LRG_293t1:c.7040C>A
LRG_293:g.44414C>A
LRG_293p1:p.Pro2347Gln
NC_000013.10:g.32929030C>A
NM_000059.3:c.7040C>A
U43746.1:n.7268C>A
p.P2347Q

Protein change:

P2347Q

Links:

dbSNP: rs80358929

NCBI 1000 Genomes Browser:

rs80358929

Molecular consequence:

NM_000059.4:c.7040C>A - 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

Recent activity

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PREDICTED: Homo sapiens uncharacterized lncRNA (LOC105373640), ncRNA
PREDICTED: Homo sapiens uncharacterized lncRNA (LOC105373640), ncRNA
gi|1034618444|ref|XR_923371.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000218177	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Oct 31, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21952622, 22711857, 29641532, 31158355 Citation Link,
SCV000906461	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 25, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21741379, 21952622, 22711857, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000218177

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Oct 31, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV000906461

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 25, 2023)

germline

clinical testing

PubMed (4)
[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

Germline mutations in candidate predisposition genes in individuals with cutaneous melanoma and at least two independent additional primary cancers.

Pritchard AL, Johansson PA, Nathan V, Howlie M, Symmons J, Palmer JM, Hayward NK.

PLoS One. 2018;13(4):e0194098. doi: 10.1371/journal.pone.0194098.

PubMed [citation]

PMID:: 29641532
PMCID:: PMC5894988

Synchronous Urothelial Bladder and Renal Malignancies. Case Report and Review of Urologic Cancers in Patients With Familial Rb Mutations.

Leinwand GZ, Greenberg JW, Sholl AB, Krane LS.

Urology. 2019 Sep;131:89-92. doi: 10.1016/j.urology.2019.05.026. Epub 2019 May 31.

PubMed [citation]

PMID:: 31158355

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV000218177.6

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

Description

The p.P2347Q variant (also known as c.7040C>A), located in coding exon 13 of the BRCA2 gene, results from a C to A substitution at nucleotide position 7040. The proline at codon 2347 is replaced by glutamine, an amino acid with similar properties. In one study, this alteration was identified in a man diagnosed with prostate cancer (Kote-Jarai Z et al. Br. J. Cancer. 2011 Oct;105:1230-4). This alteration was also observed in 1/1001 patients with non-mucinous ovarian carcinoma and classified as unclassified significance by the authors. Of note, this alteration occurred concurrently with another pathogenic BRCA1 or BRCA2 mutation in this study (Alsop K et al. J. Clin. Oncol. 2012 Jul;30:2654-63). This alteration was identified in a patient with bilateral retinoblastoma and renal cancer who was also positive for a pathogenic mutation in the RB1 gene (Leinwand GZ et al. Urology, 2019 Sep;131:89-92). This alteration was also identified in 1/1358 unrelated, non-cancer controls in a case-control study of individuals with cutaneous melanoma and at least two independent additional primary cancers (Pritchard AL et al. PLoS ONE. 2018 Apr;13:e0194098). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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, SCV000906461.4

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

Description

This missense variant replaces proline with glutamine at codon 2347 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 one individual each affected with breast, prostate and ovarian cancer (PMID: 21741379, 21952622, 22711857) and in an individual age 70 years or older without cancer in the FLOSSIES database. This variant has not been identified 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 29, 2024

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