NM_000059.4(BRCA2):c.5554G>A (p.Val1852Ile) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Jun 7, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000656609.25

Allele description [Variation Report for NM_000059.4(BRCA2):c.5554G>A (p.Val1852Ile)]

NM_000059.4(BRCA2):c.5554G>A (p.Val1852Ile)

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.5554G>A (p.Val1852Ile)

HGVS:

NC_000013.11:g.32339909G>A
NG_012772.3:g.29430G>A
NM_000059.4:c.5554G>AMANE SELECT
NP_000050.2:p.Val1852Ile
NP_000050.3:p.Val1852Ile
LRG_293t1:c.5554G>A
LRG_293:g.29430G>A
LRG_293p1:p.Val1852Ile
NC_000013.10:g.32914046G>A
NM_000059.3:c.5554G>A
U43746.1:n.5782G>A
p.V1852I

Nucleotide change:

5782G>A

Protein change:

V1852I

Links:

dbSNP: rs80358777

NCBI 1000 Genomes Browser:

rs80358777

Molecular consequence:

NM_000059.4:c.5554G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Tudor/PWWP/MBT superfamily protein [Arabidopsis thaliana]
Tudor/PWWP/MBT superfamily protein [Arabidopsis thaliana]
gi|30690738|ref|NP_198117.2|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000618094	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Dec 26, 2019)	germline	clinical testing	Citation Link,
SCV000778686	Mayo Clinic Laboratories, Mayo Clinic	no assertion criteria provided	Uncertain significance (Jun 23, 2017)	unknown	clinical testing
SCV000889072	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Jun 7, 2023)	unknown	clinical testing	PubMed (10) [See all records that cite these PMIDs] 25348012, 33875706, 32980694, 29467240, 30287823, 30415210, 23555315, 33471991, 31131967, 26467025
SCV001471808	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Uncertain significance (May 9, 2023)	germline	clinical testing	Citation Link

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Summary from all submissions

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

Citations

PubMed

Benchmarking mutation effect prediction algorithms using functionally validated cancer-related missense mutations.

Martelotto LG, Ng CK, De Filippo MR, Zhang Y, Piscuoglio S, Lim RS, Shen R, Norton L, Reis-Filho JS, Weigelt B.

Genome Biol. 2014 Oct 28;15(10):484. doi: 10.1186/s13059-014-0484-1.

PubMed [citation]

PMID:: 25348012
PMCID:: PMC4232638

Analysis of BRCA1/2 variants of unknown significance in the prospective Korean Hereditary Breast Cancer study.

Kim JH, Park S, Park HS, Park JS, Lee ST, Kim SW, Lee JW, Lee MH, Park SK, Noh WC, Choi DH, Han W, Jung SH.

Sci Rep. 2021 Apr 19;11(1):8485. doi: 10.1038/s41598-021-87792-w. Erratum in: Sci Rep. 2023 Mar 8;13(1):3874. doi: 10.1038/s41598-023-31093-x.

PubMed [citation]

PMID:: 33875706
PMCID:: PMC8055990

See all PubMed Citations (10)

Details of each submission

From GeneDx, SCV000618094.4

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

Description

This variant is associated with the following publications: (PMID: 25348012, 23555315, 10923033, 29416916, 29467240, 21520333, 30287823, 31131967)

#	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		not provided	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV000778686.1

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000889072.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

In the published literature, the variant has been reported in individuals with breast cancer (PMID: 33875706 (2021), 33471991 (2021), 30287823 (2018)), pancreatic cancer (PMID: 32980694 (2020)), and prostate cancer (PMID: 23555315 (2013)). The variant has also been identified in unaffected individuals (PMID: 33471991 (2021), 32980694 (2020), 30287823 (2018), 23555315 (2013)). The frequency of this variant in the general population, 0.00007 (9/127900 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001471808.2

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

Description

The BRCA2 c.5554G>A; p.Val1852Ile variant (rs80358777) is reported in the literature in several individuals affected with breast cancer, as well as several healthy controls (Kim 2021, Momozawa 2018). This variant is also reported in ClinVar (Variation ID: 37973). It is observed in the non-Finnish European population with an overall allele frequency of 0.007% (9/127900 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.335). A multifactorial likelihood analysis based on family history, co-segregation and co-occurrence with pathogenic variants suggests that the p.Val1852Ile variant is unlikely to cause disease (Parsons 2019). Due to limited information, the clinical significance of the p.Val1852Ile variant is uncertain at this time. References: Kim JH et al. Analysis of BRCA1/2 variants of unknown significance in the prospective Korean Hereditary Breast Cancer study. Sci Rep. 2021 Apr 19;11(1):8485. PMID: 33875706. Parsons MT et al. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. Hum Mutat. 2019 Sep;40(9):1557-1578. PMID: 31131967. Momozawa Y et al. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Nat Commun. 2018 Oct 4;9(1):4083. PMID: 30287823.

#	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: Nov 3, 2024

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