NM_000179.3(MSH6):c.2253T>G (p.Asn751Lys) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 6, 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:: RCV003761094.2

Allele description [Variation Report for NM_000179.3(MSH6):c.2253T>G (p.Asn751Lys)]

NM_000179.3(MSH6):c.2253T>G (p.Asn751Lys)

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.2253T>G (p.Asn751Lys)

HGVS:

NC_000002.12:g.47800236T>G
NG_007111.1:g.22090T>G
NM_000179.3:c.2253T>GMANE SELECT
NM_001281492.2:c.1863T>G
NM_001281493.2:c.1347T>G
NM_001281494.2:c.1347T>G
NM_001406795.1:c.2349T>G
NM_001406796.1:c.2253T>G
NM_001406797.1:c.1956T>G
NM_001406798.1:c.2253T>G
NM_001406799.1:c.1728T>G
NM_001406800.1:c.2253T>G
NM_001406801.1:c.1956T>G
NM_001406802.1:c.2349T>G
NM_001406803.1:c.2253T>G
NM_001406804.1:c.2175T>G
NM_001406805.1:c.1956T>G
NM_001406806.1:c.1728T>G
NM_001406807.1:c.1728T>G
NM_001406808.1:c.2253T>G
NM_001406809.1:c.2253T>G
NM_001406811.1:c.1347T>G
NM_001406812.1:c.1347T>G
NM_001406813.1:c.2259T>G
NM_001406814.1:c.1347T>G
NM_001406815.1:c.1347T>G
NM_001406816.1:c.1347T>G
NM_001406817.1:c.1606+647T>G
NM_001406818.1:c.1956T>G
NM_001406819.1:c.1956T>G
NM_001406820.1:c.1956T>G
NM_001406821.1:c.1956T>G
NM_001406822.1:c.1956T>G
NM_001406823.1:c.1347T>G
NM_001406824.1:c.1956T>G
NM_001406825.1:c.1956T>G
NM_001406826.1:c.2085T>G
NM_001406827.1:c.1956T>G
NM_001406828.1:c.1956T>G
NM_001406829.1:c.1347T>G
NM_001406830.1:c.1956T>G
NM_001407362.1:c.628-430T>G
NP_000170.1:p.Asn751Lys
NP_000170.1:p.Asn751Lys
NP_001268421.1:p.Asn621Lys
NP_001268422.1:p.Asn449Lys
NP_001268423.1:p.Asn449Lys
NP_001393724.1:p.Asn783Lys
NP_001393725.1:p.Asn751Lys
NP_001393726.1:p.Asn652Lys
NP_001393727.1:p.Asn751Lys
NP_001393728.1:p.Asn576Lys
NP_001393729.1:p.Asn751Lys
NP_001393730.1:p.Asn652Lys
NP_001393731.1:p.Asn783Lys
NP_001393732.1:p.Asn751Lys
NP_001393733.1:p.Asn725Lys
NP_001393734.1:p.Asn652Lys
NP_001393735.1:p.Asn576Lys
NP_001393736.1:p.Asn576Lys
NP_001393737.1:p.Asn751Lys
NP_001393738.1:p.Asn751Lys
NP_001393740.1:p.Asn449Lys
NP_001393741.1:p.Asn449Lys
NP_001393742.1:p.Asn753Lys
NP_001393743.1:p.Asn449Lys
NP_001393744.1:p.Asn449Lys
NP_001393745.1:p.Asn449Lys
NP_001393747.1:p.Asn652Lys
NP_001393748.1:p.Asn652Lys
NP_001393749.1:p.Asn652Lys
NP_001393750.1:p.Asn652Lys
NP_001393751.1:p.Asn652Lys
NP_001393752.1:p.Asn449Lys
NP_001393753.1:p.Asn652Lys
NP_001393754.1:p.Asn652Lys
NP_001393755.1:p.Asn695Lys
NP_001393756.1:p.Asn652Lys
NP_001393757.1:p.Asn652Lys
NP_001393758.1:p.Asn449Lys
NP_001393759.1:p.Asn652Lys
LRG_219t1:c.2253T>G
LRG_219:g.22090T>G
LRG_219p1:p.Asn751Lys
NC_000002.11:g.48027375T>G
NM_000179.2:c.2253T>G
NR_176256.1:n.1115T>G
NR_176257.1:n.2342T>G
NR_176258.1:n.2342T>G
NR_176259.1:n.2342T>G
NR_176261.1:n.2342T>G

Protein change:

N449K

Molecular consequence:

NM_001406817.1:c.1606+647T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001407362.1:c.628-430T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000179.3:c.2253T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.1863T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.1347T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.1347T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406795.1:c.2349T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406796.1:c.2253T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406797.1:c.1956T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406798.1:c.2253T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406799.1:c.1728T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406800.1:c.2253T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406801.1:c.1956T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406802.1:c.2349T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406803.1:c.2253T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406804.1:c.2175T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406805.1:c.1956T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406806.1:c.1728T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406807.1:c.1728T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406808.1:c.2253T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406809.1:c.2253T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406811.1:c.1347T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406812.1:c.1347T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406813.1:c.2259T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406814.1:c.1347T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406815.1:c.1347T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406816.1:c.1347T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406818.1:c.1956T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406819.1:c.1956T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406820.1:c.1956T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406821.1:c.1956T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406822.1:c.1956T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406823.1:c.1347T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406824.1:c.1956T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406825.1:c.1956T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406826.1:c.2085T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406827.1:c.1956T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406828.1:c.1956T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406829.1:c.1347T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406830.1:c.1956T>G - missense variant - [Sequence Ontology: SO:0001583]
NR_176256.1:n.1115T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176257.1:n.2342T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176258.1:n.2342T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176259.1:n.2342T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176261.1:n.2342T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

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

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Homo sapiens centlein, centrosomal protein (CNTLN), transcript variant 1, mRNA
Homo sapiens centlein, centrosomal protein (CNTLN), transcript variant 1, mRNA
gi|110815814|ref|NM_017738.2|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004422065	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 6, 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

SCV004422065

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 6, 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, SCV004422065.1

#	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 not 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 (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 751 of the MSH6 protein (p.Asn751Lys).

#	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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