NM_000179.2(MSH6):c.2633T>C (p.Val878Ala)

NM_000179.2(MSH6):c.2633T>C (p.Val878Ala)

Variant type:
single nucleotide variant
Cytogenetic location:
2p16
Genomic location:
  • Chr2:48027755 (on Assembly GRCh37)
  • Chr2:47800616 (on Assembly GRCh38)
Protein change:
V878A
HGVS:
  • NG_007111.1:g.22470T>C
  • NM_000179.2:c.2633T>C
  • NC_000002.12:g.47800616T>C
  • NC_000002.11:g.48027755T>C
  • NP_000170.1:p.Val878Ala
  • LRG_219p1:p.Val878Ala
  • LRG_219t1:c.2633T>C
  • LRG_219:g.22470T>C
Links:
NCBI 1000 Genomes Browser:
rs2020912
Molecular consequence:
NM_000179.2:c.2633T>C: missense variant [Sequence Ontology SO:0001583]
Allele frequency:
  • GO-ESP 0.00546 (C)
  • GMAF 0.00510 (C)

Clinical significance

NM_000179.2(MSH6):c.2633T>C (p.Val878Ala)

Clinical significance:
Benign/Likely benign
Benign;Pathogenic;Uncertain significance
Review status:
(3/4)3 stars out of maximum of 4 stars
reviewed by expert panel
Number of submission(s):
7
Condition(s)
  • Colon cancer, hereditary nonpolyposis, type 5
  • Lynch syndrome[MedGen]
  • AllHighlyPenetrant
See supporting ClinVar records

Recent Activity

Assertion and evidence details

Germline

Clinical significance
(Last evaluated)
Review status
(Assertion method)
Collection methodCondition(s)
(Mode of inheritance)
OriginCitationsSubmitter
(Last submitted)
Submission accession
Benign
(Sep 5, 2013)
reviewed by expert panel
(evidence-based review)
researchgermlineCitation LinkInSiGHT
(Dec 18, 2013)
SCV000107978
Benign
(Mar 27, 2014)
classified by single submitter
(clinical testing)
clinical testinggermlineInvitae
(Mar 27, 2014)
SCV000153945
Pathogenic
(Feb 9, 2012)
classified by single submitter
(literature only)
literature only
  • Colon cancer, hereditary nonpolyposis, type 5
germlinePubMed (1)
OMIM
(Dec 30, 2010)
SCV000029704
Uncertain significance
(Aug 18, 2011)
classified by single submitter
(clinical testing, literature only)
clinical testing, literature only
  • Lynch syndrome (Autosomal dominant inheritance)[MedGen]
germlinePubMed (10)
LabCorp
(Aug 18, 2011)
SCV000052931
Benign
(Jul 13, 2012)
classified by single submitter
(research)
research
  • not provided
germlineBiesecker Laboratory - ClinSeq Project, NHGRI
(Jul 15, 2012)
SCV000043358
Benign
(Oct 11, 2013)
classified by single submitter
(clinical testing)
clinical testing
  • not provided
germlineGeneDx
(Jun 10, 2014)
SCV000170356
not provided
(Sep 19, 2013)
not classified by submitter
(reference population)
reference population
  • AllHighlyPenetrant
germlineITMI
(May 29, 2014)
SCV000085777

Summary

FamiliesIndividualsSegregationAllele originEthnicityGeographic origin
not provided29not providedgermline, African, African_European, Central_Asian, East_Asian, European, Hispanic, Whole_cohort, not providednot provided

Biesecker Laboratory - ClinSeq Project

Observations

FamiliesIndividualsSegregationAllele originObserved phenotypesEthnicityGeographic originCollection methodDescription
not provided2not providedgermlinenot providednot providednot providedresearchSee description

GeneDx

Observations

FamiliesIndividualsSegregationAllele originObserved phenotypesEthnicityGeographic originCollection methodDescription
not providednot providednot providedgermlinenot providednot providednot providedclinical testingSee description

ITMI

Observations

FamiliesIndividualsSegregationAllele originObserved phenotypesEthnicityGeographic originCollection method
not providednot providednot providedgermlinenot providedAfricannot providedreference population
not providednot providednot providedgermlinenot providedAfrican_Europeannot providedreference population
not providednot providednot providedgermlinenot providedCentral_Asiannot providedreference population
not providednot providednot providedgermlinenot providedEast_Asiannot providedreference population
not providednot providednot providedgermlinenot providedEuropeannot providedreference population
not providednot providednot providedgermlinenot providedHispanicnot providedreference population
not providednot providednot providedgermlinenot providedWhole_cohortnot providedreference population

InSiGHT

Observations

FamiliesIndividualsSegregationAllele originObserved phenotypesEthnicityGeographic originCollection methodDescription
not providednot providednot providedgermlinenot providednot providednot providedresearchSee description

Invitae

Observations

FamiliesIndividualsSegregationAllele originObserved phenotypesEthnicityGeographic originCollection methodDescription
not providednot providednot providedgermlinenot providednot providednot providedclinical testingSee description

LabCorp

Observations

FamiliesIndividualsSegregationAllele originObserved phenotypesEthnicityGeographic originCollection method
not provided1not providedgermlinenot providednot providednot providedclinical testing

Data published from literature

FamiliesIndividualsSegregationsAllele originCitations
not provided1not providedgermline
not provided1not providedgermline
not provided1not providedgermline
not provided2not providedgermline
not provided2not providedgermline
not provided3not providedgermline
not provided3not providedgermline
not provided4not providedgermline
not provided4not providedgermline
not provided5not providedgermline

Description

Two patients diagnosed with CRC and endometrial cancer; Family B, pt III:2 and Family C, pt III:3 (ages 70 and 72 respectively), meet the Bethesda criteria for HNPCC; both pts are heterozygous for the variant and A20V; 1 pt previously reported by Wijnen_MSH6_NatGen_1999, thus occurrence was not counted; in both families, there are member(s) diagnosed with HNPCC-related tumors who do not carry the variant and do not meet criteria for HNPCC diagnosis (n=5); not detected in controls.
Variant was detected in a patient diagnosed with HNPCC; controls not tested.
The variant was detected in a female, age 34, diagnosed with CRC who meets the Bethesda criteria of HNPCC diagnosis; no family history of cancer; authors suggest this variant should be classified as a polymorphism; variant was detected in controls (see pbGP).
The variant was detected twice in families that met the Amsterdam or Bethesda criteria for HNPCC; The authors note that although the variant was previously reported as a possible disease-causing variant, “In our study, the Val878Ala substitution was found in 4 healthy control persons (Table V), and it was been detected in healthy persons by the SNP consortium. We therefore suggest that it should be definitively classified as a polymorphism.”; detected in controls (see pbGP).
The variant was detected in family #94 diagnosed with HNPCC; Proband and his sister are heterozygous for the variant and K618A in the MLH1 gene (unclassified variant); the proband was clinically diagnosed with CRC at age 51 and prostate cancer at age 52; Proband’s sister was diagnosed with endometrial cancer at age 45; tumor from the probands did not express MSH6; not detected in controls (see pbGP).
The variant was detected in three families who meet the Bethesda criteria for HNPCC diagnosis; total frequency was not specified, thus one occurrence was counted for each family; authors list that the variant was not observed in the general population, but do not provide any details in regards to frequency or control cohort size.
The variant was detected in three pts that meet the Bethesda criteria for HNPCC diagnosis; authorship overlap with Wu_MSH6_NatGen_2001; occurrences in Wu et al. (2001) were not previously counted due to a lack of clinical description; clinical data provided here, thus all occurrences were counted; not detected in controls (see pbGP).
The variant was detected in family #74 diagnosed with HNPCC; Progand, his mother, brother and sister are all heterozygous for the variant and all were diagnosed with one or more HNPCC-related tumor(s) under the age of 50; not detected in controls (see pbGP).
Variant was detected in 5 patients diagnosed with HNPCC; Pt 58 is heterozygous for the variant and c.3207G>T; Pt 50 is heterozygous for variant and MLH1 c.381-40_381-37delAGAT; authors describe the variant as “unknown clinical significance” (see supplemental data); One occurrence may have been previously reported by Plaschke_MSH6_JCO_2004, thus only 4 occurrences counted; unknown if detected in controls.
The variant was detected in 5 patients diagnosed with HNPCC; the authors suggest that the variant has no relevance to cancer risk based on similar frequencies seen in cases and controls; detected in controls (see pbGP).

OMIM

Data published from literature

FamiliesIndividualsSegregationsAllele originCitations
not providednot providednot providedgermline

Description

In 2 patients with HNPCC who had the same mutation in the MLH3 gene (glu1451 to lys; 604395), Wu et al. (2001) found 2 mutations in the MSH6 gene. One was a val878-to-ala mutation; the other was an insertion of a T at nucleotide position 650.

Last Updated: Aug 25, 2014

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