NM_000179.3(MSH6):c.1474A>G (p.Met492Val) AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Jan 21, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000115374.10

Allele description [Variation Report for NM_000179.3(MSH6):c.1474A>G (p.Met492Val)]

NM_000179.3(MSH6):c.1474A>G (p.Met492Val)

Gene:
MSH6:mutS homolog 6 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2p16.3
Genomic location:
Preferred name:
NM_000179.3(MSH6):c.1474A>G (p.Met492Val)
Other names:
p.M492V:ATG>GTG
HGVS:
  • NC_000002.12:g.47799457A>G
  • NG_007111.1:g.21311A>G
  • NM_000179.2:c.1474A>G
  • NM_000179.3:c.1474A>GMANE SELECT
  • NM_001281492.1:c.1084A>G
  • NM_001281493.1:c.568A>G
  • NM_001281494.1:c.568A>G
  • NP_000170.1:p.Met492Val
  • NP_000170.1:p.Met492Val
  • NP_001268421.1:p.Met362Val
  • NP_001268422.1:p.Met190Val
  • NP_001268423.1:p.Met190Val
  • LRG_219t1:c.1474A>G
  • LRG_219:g.21311A>G
  • LRG_219p1:p.Met492Val
  • NC_000002.11:g.48026596A>G
  • P52701:p.Met492Val
  • p.M492V
Protein change:
M190V
Links:
UniProtKB: P52701#VAR_042275; dbSNP: rs61754783
NCBI 1000 Genomes Browser:
rs61754783
Molecular consequence:
  • NM_000179.2:c.1474A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000179.3:c.1474A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281492.1:c.1084A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281493.1:c.568A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281494.1:c.568A>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000185429Ambry Geneticscriteria provided, single submitter
Uncertain significance
(Jan 21, 2020)
germlineclinical testing

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

Citation Link,

SCV000902794Color Health, Inccriteria provided, single submitter
Likely benign
(Mar 10, 2016)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma.

Shindo K, Yu J, Suenaga M, Fesharakizadeh S, Cho C, Macgregor-Das A, Siddiqui A, Witmer PD, Tamura K, Song TJ, Navarro Almario JA, Brant A, Borges M, Ford M, Barkley T, He J, Weiss MJ, Wolfgang CL, Roberts NJ, Hruban RH, Klein AP, Goggins M.

J Clin Oncol. 2017 Oct 20;35(30):3382-3390. doi: 10.1200/JCO.2017.72.3502. Epub 2017 Aug 2.

PubMed [citation]
PMID:
28767289
PMCID:
PMC5648172

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 Ambry Genetics, SCV000185429.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

The p.M492V variant (also known as c.1474A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 1474. The methionine at codon 492 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported as a variant of unknown significance in multiple individuals, including one family from the Danish HNPCC-registry (Nilbert M et al. Fam. Cancer. 2009 Jun;8:75-83), one family meeting Amsterdam criteria (Wagner A et al. Am. J. Hum. Genet. 2003 May;72:1088-100), two unrelated individuals from HNPCC families with colon tumors demonstrating normal MSH6 expression on IHC studies (Okkels H et al. Appl. Immunohistochem. Mol. Morphol. 2012 Oct;20:470-7), and a patient diagnosed with a pancreatic neuroendocrine tumor at age 57 (Shindo K et al. J. Clin. Oncol. 2017 Oct;35:3382-3390). In addition, one functional study reported this variant to be proficient in in vitro mismatch repair (MMR) activity (Drost M et al. Hum. Mutat. 2012 Mar;33:488-94). This amino acid position is highly 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

From Color Health, Inc, SCV000902794.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 7, 2021

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