NM_000179.3(MSH6):c.3692T>A (p.Val1231Asp) AND Hereditary nonpolyposis colorectal neoplasms

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 17, 2021
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:: RCV001916979.3

Allele description

NM_000179.3(MSH6):c.3692T>A (p.Val1231Asp)

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.3692T>A (p.Val1231Asp)

HGVS:

NC_000002.12:g.47806249T>A
NG_007111.1:g.28103T>A
NG_008397.1:g.104427A>T
NM_000179.3:c.3692T>AMANE SELECT
NM_001281492.2:c.3302T>A
NM_001281493.2:c.2786T>A
NM_001281494.2:c.2786T>A
NP_000170.1:p.Val1231Asp
NP_001268421.1:p.Val1101Asp
NP_001268422.1:p.Val929Asp
NP_001268423.1:p.Val929Asp
LRG_219t1:c.3692T>A
LRG_219:g.28103T>A
NC_000002.11:g.48033388T>A
NM_000179.2:c.3692T>A

Protein change:

V1101D

Links:

dbSNP: rs1221659275

NCBI 1000 Genomes Browser:

rs1221659275

Molecular consequence:

NM_000179.3:c.3692T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.3302T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.2786T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.2786T>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

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AJR76048 (0)
ClinVar
Homo sapiens epiplakin 1 (EPPK1), mRNA
Homo sapiens epiplakin 1 (EPPK1), mRNA
gi|13876385|ref|NM_031308.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002193182	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 17, 2021)	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

SCV002193182

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 17, 2021)

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 Invitae, SCV002193182.3

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

Description

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) performed at Invitae indicates that this missense variant is expected to disrupt MSH6 protein function. This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with aspartic acid at codon 1231 of the MSH6 protein (p.Val1231Asp). The valine residue is highly conserved and there is a large physicochemical difference between valine and aspartic acid.

#	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: May 1, 2024

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