NM_000179.3(MSH6):c.2827G>T (p.Asp943Tyr) AND Hereditary nonpolyposis colorectal neoplasms

Clinical significance:Uncertain significance (Last evaluated: Oct 19, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000205918.8

Allele description [Variation Report for NM_000179.3(MSH6):c.2827G>T (p.Asp943Tyr)]

NM_000179.3(MSH6):c.2827G>T (p.Asp943Tyr)

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.2827G>T (p.Asp943Tyr)
Other names:
p.D943Y:GAC>TAC
HGVS:
  • NC_000002.12:g.47800810G>T
  • NG_007111.1:g.22664G>T
  • NM_000179.3:c.2827G>TMANE SELECT
  • NM_001281492.2:c.2437G>T
  • NM_001281493.2:c.1921G>T
  • NM_001281494.2:c.1921G>T
  • NP_000170.1:p.Asp943Tyr
  • NP_000170.1:p.Asp943Tyr
  • NP_001268421.1:p.Asp813Tyr
  • NP_001268422.1:p.Asp641Tyr
  • NP_001268423.1:p.Asp641Tyr
  • LRG_219t1:c.2827G>T
  • LRG_219:g.22664G>T
  • LRG_219p1:p.Asp943Tyr
  • NC_000002.11:g.48027949G>T
  • NM_000179.2:c.2827G>T
  • p.D943Y
Protein change:
D641Y
Links:
dbSNP: rs143520357
NCBI 1000 Genomes Browser:
rs143520357
Molecular consequence:
  • NM_000179.3:c.2827G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281492.2:c.2437G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281493.2:c.1921G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281494.2:c.1921G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary nonpolyposis colorectal neoplasms
Identifiers:
MedGen: C0009405; Orphanet: 443090

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000261184Invitaecriteria provided, single submitter
Uncertain significance
(Oct 19, 2020)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.

Tung N, Battelli C, Allen B, Kaldate R, Bhatnagar S, Bowles K, Timms K, Garber JE, Herold C, Ellisen L, Krejdovsky J, DeLeonardis K, Sedgwick K, Soltis K, Roa B, Wenstrup RJ, Hartman AR.

Cancer. 2015 Jan 1;121(1):25-33. doi: 10.1002/cncr.29010. Epub 2014 Sep 3.

PubMed [citation]
PMID:
25186627

Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer.

Grant RC, Selander I, Connor AA, Selvarajah S, Borgida A, Briollais L, Petersen GM, Lerner-Ellis J, Holter S, Gallinger S.

Gastroenterology. 2015 Mar;148(3):556-64. doi: 10.1053/j.gastro.2014.11.042. Epub 2014 Dec 2.

PubMed [citation]
PMID:
25479140
PMCID:
PMC4339623
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000261184.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces aspartic acid with tyrosine at codon 943 of the MSH6 protein (p.Asp943Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is present in population databases (rs143520357, ExAC 0.006%). This variant has been reported in individuals affected with breast cancer (PMID: 25186627) and pancreatic cancer (PMID: 25479140). ClinVar contains an entry for this variant (Variation ID: 142495). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). However, an algorithm developed specifically for the MSH6 protein suggests that this missense change is likely to be deleterious (PMID: 23621914). None of these predictions have been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 5

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Dec 4, 2021

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