NM_000059.4(BRCA2):c.10250A>G (p.Tyr3417Cys) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: May 14, 2022
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:: RCV000160263.7

Allele description [Variation Report for NM_000059.4(BRCA2):c.10250A>G (p.Tyr3417Cys)]

NM_000059.4(BRCA2):c.10250A>G (p.Tyr3417Cys)

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.10250A>G (p.Tyr3417Cys)

Other names:

p.Y3417C:TAT>TGT

HGVS:

NC_000013.11:g.32398763A>G
NG_012772.3:g.88284A>G
NM_000059.4:c.10250A>GMANE SELECT
NP_000050.2:p.Tyr3417Cys
NP_000050.3:p.Tyr3417Cys
LRG_293t1:c.10250A>G
LRG_293:g.88284A>G
LRG_293p1:p.Tyr3417Cys
NC_000013.10:g.32972900A>G
NM_000059.3:c.10250A>G

Protein change:

Y3417C

Links:

dbSNP: rs730881600

NCBI 1000 Genomes Browser:

rs730881600

Molecular consequence:

NM_000059.4:c.10250A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000210702	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely benign (Feb 24, 2016)	germline	clinical testing	Citation Link,
SCV001363361	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (May 14, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000210702

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely benign
(Feb 24, 2016)

germline

clinical testing

Citation Link,

SCV001363361

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(May 14, 2022)

germline

clinical testing

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

Citation Link

Help

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

Citations

PubMed

BRCA1 and BRCA2 mutational profile and prevalence in hereditary breast and ovarian cancer (HBOC) probands from Southern Brazil: Are international testing criteria appropriate for this specific population?

Alemar B, Gregório C, Herzog J, Matzenbacher Bittar C, Brinckmann Oliveira Netto C, Artigalas O, Schwartz IVD, Coffa J, Alves Camey S, Weitzel J, Ashton-Prolla P.

PLoS One. 2017;12(11):e0187630. doi: 10.1371/journal.pone.0187630. Erratum in: PLoS One. 2018 May 11;13(5):e0197529.

PubMed [citation]

PMID:: 29161300
PMCID:: PMC5697861

Details of each submission

From GeneDx, SCV000210702.10

#	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 considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001363361.2

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

Description

Variant summary: BRCA2 c.10250A>G (p.Tyr3417Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250062 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.10250A>G has been reported in the literature as a VUS in at-least one individual affected with Hereditary Breast And Ovarian Cancer (example, Alemar_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=2; Likely Benign, n=2). Based on the evidence outlined above, the variant was classified as 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: Jun 2, 2024

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