NM_000179.3(MSH6):c.2288A>G (p.Asp763Gly) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Apr 12, 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:: RCV000477003.10

Allele description [Variation Report for NM_000179.3(MSH6):c.2288A>G (p.Asp763Gly)]

NM_000179.3(MSH6):c.2288A>G (p.Asp763Gly)

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.2288A>G (p.Asp763Gly)

HGVS:

NC_000002.12:g.47800271A>G
NG_007111.1:g.22125A>G
NM_000179.3:c.2288A>GMANE SELECT
NM_001281492.2:c.1898A>G
NM_001281493.2:c.1382A>G
NM_001281494.2:c.1382A>G
NP_000170.1:p.Asp763Gly
NP_000170.1:p.Asp763Gly
NP_001268421.1:p.Asp633Gly
NP_001268422.1:p.Asp461Gly
NP_001268423.1:p.Asp461Gly
LRG_219t1:c.2288A>G
LRG_219:g.22125A>G
LRG_219p1:p.Asp763Gly
NC_000002.11:g.48027410A>G
NM_000179.2:c.2288A>G

Protein change:

D461G

Links:

dbSNP: rs1060502913

NCBI 1000 Genomes Browser:

rs1060502913

Molecular consequence:

NM_000179.3:c.2288A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.1898A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.1382A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.1382A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

Recent activity

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Danio rerio phosphoinositide-3-kinase interacting protein 1 (pik3ip1), mRNA
Danio rerio phosphoinositide-3-kinase interacting protein 1 (pik3ip1), mRNA
gi|2749856424|ref|NM_198374.2|

Nucleotide
Danio rerio zgc:56095, mRNA (cDNA clone MGC:56095 IMAGE:5410741), complete cds
Danio rerio zgc:56095, mRNA (cDNA clone MGC:56095 IMAGE:5410741), complete cds
gi|28279153|gb|BC045905.1|

Nucleotide
thoc5 THO complex 5 [Danio rerio]
thoc5 THO complex 5 [Danio rerio]
Gene ID:325064

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000551156	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 12, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000551156

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 12, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000551156.7

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

Description

This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. ClinVar contains an entry for this variant (Variation ID: 410460). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 763 of the MSH6 protein (p.Asp763Gly).

#	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: Sep 29, 2024

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