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NM_000179.3(MSH6):c.3557G>A (p.Gly1186Asp) AND Lynch syndrome

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Nov 30, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV003997530.2

Allele description [Variation Report for NM_000179.3(MSH6):c.3557G>A (p.Gly1186Asp)]

NM_000179.3(MSH6):c.3557G>A (p.Gly1186Asp)

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.3557G>A (p.Gly1186Asp)
HGVS:
  • NC_000002.12:g.47805618G>A
  • NG_007111.1:g.27472G>A
  • NG_008397.1:g.105058C>T
  • NM_000179.3:c.3557G>AMANE SELECT
  • NM_001281492.2:c.3167G>A
  • NM_001281493.2:c.2651G>A
  • NM_001281494.2:c.2651G>A
  • NP_000170.1:p.Gly1186Asp
  • NP_000170.1:p.Gly1186Asp
  • NP_001268421.1:p.Gly1056Asp
  • NP_001268422.1:p.Gly884Asp
  • NP_001268423.1:p.Gly884Asp
  • LRG_219t1:c.3557G>A
  • LRG_219:g.27472G>A
  • LRG_219p1:p.Gly1186Asp
  • NC_000002.11:g.48032757G>A
  • NM_000179.2:c.3557G>A
  • p.G1186D
Protein change:
G1056D
Links:
dbSNP: rs587781690
NCBI 1000 Genomes Browser:
rs587781690
Molecular consequence:
  • NM_000179.3:c.3557G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281492.2:c.3167G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281493.2:c.2651G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281494.2:c.2651G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
6

Condition(s)

Name:
Lynch syndrome
Identifiers:
MONDO: MONDO:0005835; MedGen: C4552100

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV004835091All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain Significance
(Nov 30, 2023)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown6not providednot provided108544not providedclinical testing

Citations

PubMed

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

Breast Cancer Association Consortium., Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, Wahlström C, Pooley KA, Parsons MT, Fortuno C, Wang Q, Bolla MK, Dennis J, Keeman R, Alonso MR, Álvarez N, Herraez B, Fernandez V, Núñez-Torres R, Osorio A, Valcich J, Li M, et al.

N Engl J Med. 2021 Feb 4;384(5):428-439. doi: 10.1056/NEJMoa1913948. Epub 2021 Jan 20.

PubMed [citation]
PMID:
33471991
PMCID:
PMC7611105

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 All of Us Research Program, National Institutes of Health, SCV004835091.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided6not providednot providedclinical testing PubMed (2)

Description

This missense variant replaces glycine with aspartic acid at codon 1186 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with Lynch syndrome or colorectal cancer cancer in the literature. In a large breast cancer case-control study, This variant has been observed in 2/60466 cases and 0/53461 unaffected controls (PMID: 33471991). This variant has been identified in 5/249444 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided6not providednot providednot provided

Last Updated: Oct 8, 2024