NM_000179.3(MSH6):c.2425G>A (p.Val809Ile) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 25, 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:: RCV003595587.2

Allele description [Variation Report for NM_000179.3(MSH6):c.2425G>A (p.Val809Ile)]

NM_000179.3(MSH6):c.2425G>A (p.Val809Ile)

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.2425G>A (p.Val809Ile)

HGVS:

NC_000002.12:g.47800408G>A
NG_007111.1:g.22262G>A
NM_000179.3:c.2425G>AMANE SELECT
NM_001281492.2:c.2035G>A
NM_001281493.2:c.1519G>A
NM_001281494.2:c.1519G>A
NM_001406795.1:c.2521G>A
NM_001406796.1:c.2425G>A
NM_001406797.1:c.2128G>A
NM_001406798.1:c.2425G>A
NM_001406799.1:c.1900G>A
NM_001406800.1:c.2425G>A
NM_001406801.1:c.2128G>A
NM_001406802.1:c.2521G>A
NM_001406803.1:c.2308+117G>A
NM_001406804.1:c.2347G>A
NM_001406805.1:c.2128G>A
NM_001406806.1:c.1900G>A
NM_001406807.1:c.1900G>A
NM_001406808.1:c.2425G>A
NM_001406809.1:c.2425G>A
NM_001406811.1:c.1519G>A
NM_001406812.1:c.1519G>A
NM_001406813.1:c.2431G>A
NM_001406814.1:c.1519G>A
NM_001406815.1:c.1519G>A
NM_001406816.1:c.1519G>A
NM_001406817.1:c.1606+819G>A
NM_001406818.1:c.2128G>A
NM_001406819.1:c.2128G>A
NM_001406820.1:c.2128G>A
NM_001406821.1:c.2128G>A
NM_001406822.1:c.2128G>A
NM_001406823.1:c.1519G>A
NM_001406824.1:c.2128G>A
NM_001406825.1:c.2128G>A
NM_001406826.1:c.2257G>A
NM_001406827.1:c.2128G>A
NM_001406828.1:c.2128G>A
NM_001406829.1:c.1519G>A
NM_001406830.1:c.2128G>A
NM_001407362.1:c.628-258G>A
NP_000170.1:p.Val809Ile
NP_000170.1:p.Val809Ile
NP_001268421.1:p.Val679Ile
NP_001268422.1:p.Val507Ile
NP_001268423.1:p.Val507Ile
NP_001393724.1:p.Val841Ile
NP_001393725.1:p.Val809Ile
NP_001393726.1:p.Val710Ile
NP_001393727.1:p.Val809Ile
NP_001393728.1:p.Val634Ile
NP_001393729.1:p.Val809Ile
NP_001393730.1:p.Val710Ile
NP_001393731.1:p.Val841Ile
NP_001393733.1:p.Val783Ile
NP_001393734.1:p.Val710Ile
NP_001393735.1:p.Val634Ile
NP_001393736.1:p.Val634Ile
NP_001393737.1:p.Val809Ile
NP_001393738.1:p.Val809Ile
NP_001393740.1:p.Val507Ile
NP_001393741.1:p.Val507Ile
NP_001393742.1:p.Val811Ile
NP_001393743.1:p.Val507Ile
NP_001393744.1:p.Val507Ile
NP_001393745.1:p.Val507Ile
NP_001393747.1:p.Val710Ile
NP_001393748.1:p.Val710Ile
NP_001393749.1:p.Val710Ile
NP_001393750.1:p.Val710Ile
NP_001393751.1:p.Val710Ile
NP_001393752.1:p.Val507Ile
NP_001393753.1:p.Val710Ile
NP_001393754.1:p.Val710Ile
NP_001393755.1:p.Val753Ile
NP_001393756.1:p.Val710Ile
NP_001393757.1:p.Val710Ile
NP_001393758.1:p.Val507Ile
NP_001393759.1:p.Val710Ile
LRG_219t1:c.2425G>A
LRG_219:g.22262G>A
LRG_219p1:p.Val809Ile
NC_000002.11:g.48027547G>A
NM_000179.2:c.2425G>A
NR_176256.1:n.1287G>A
NR_176257.1:n.2514G>A
NR_176258.1:n.2514G>A
NR_176259.1:n.2514G>A
NR_176261.1:n.2514G>A

Protein change:

V507I

Molecular consequence:

NM_001406803.1:c.2308+117G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001406817.1:c.1606+819G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001407362.1:c.628-258G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000179.3:c.2425G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.2035G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.1519G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.1519G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406795.1:c.2521G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406796.1:c.2425G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406797.1:c.2128G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406798.1:c.2425G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406799.1:c.1900G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406800.1:c.2425G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406801.1:c.2128G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406802.1:c.2521G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406804.1:c.2347G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406805.1:c.2128G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406806.1:c.1900G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406807.1:c.1900G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406808.1:c.2425G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406809.1:c.2425G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406811.1:c.1519G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406812.1:c.1519G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406813.1:c.2431G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406814.1:c.1519G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406815.1:c.1519G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406816.1:c.1519G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406818.1:c.2128G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406819.1:c.2128G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406820.1:c.2128G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406821.1:c.2128G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406822.1:c.2128G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406823.1:c.1519G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406824.1:c.2128G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406825.1:c.2128G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406826.1:c.2257G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406827.1:c.2128G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406828.1:c.2128G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406829.1:c.1519G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406830.1:c.2128G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_176256.1:n.1287G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176257.1:n.2514G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176258.1:n.2514G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176259.1:n.2514G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176261.1:n.2514G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

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

Recent activity

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Distichodus noboli voucher t-96-9536 D-loop, partial sequence; mitochondrial
Distichodus noboli voucher t-96-9536 D-loop, partial sequence; mitochondrial
gi|1839270915|gb|MT301525.1|

Nucleotide
Distichodus noboli voucher t-65-6424 SH3 and PX domain-containing 3-like protein...
Distichodus noboli voucher t-65-6424 SH3 and PX domain-containing 3-like protein (SH3PX3) gene, partial cds
gi|1839270678|gb|MT301363.1|

Nucleotide
Mus musculus MAGE family member E2 (Magee2), mRNA
Mus musculus MAGE family member E2 (Magee2), mRNA
gi|148352327|ref|NM_053206.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004293914	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 25, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28135145, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004293914

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 25, 2023)

germline

clinical testing

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

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

Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer.

Yurgelun MB, Kulke MH, Fuchs CS, Allen BA, Uno H, Hornick JL, Ukaegbu CI, Brais LK, McNamara PG, Mayer RJ, Schrag D, Meyerhardt JA, Ng K, Kidd J, Singh N, Hartman AR, Wenstrup RJ, Syngal S.

J Clin Oncol. 2017 Apr 1;35(10):1086-1095. doi: 10.1200/JCO.2016.71.0012. Epub 2017 Jan 30.

PubMed [citation]

PMID:: 28135145
PMCID:: PMC5455355

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, SCV004293914.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

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 not expected to disrupt MSH6 protein function. This missense change has been observed in individual(s) with colorectal cancer (PMID: 28135145). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 809 of the MSH6 protein (p.Val809Ile).

#	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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