NM_000179.3(MSH6):c.2299A>C (p.Thr767Pro) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jul 22, 2022
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:: RCV002851664.3

Allele description [Variation Report for NM_000179.3(MSH6):c.2299A>C (p.Thr767Pro)]

NM_000179.3(MSH6):c.2299A>C (p.Thr767Pro)

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.2299A>C (p.Thr767Pro)

HGVS:

NC_000002.12:g.47800282A>C
NG_007111.1:g.22136A>C
NM_000179.3:c.2299A>CMANE SELECT
NM_001281492.2:c.1909A>C
NM_001281493.2:c.1393A>C
NM_001281494.2:c.1393A>C
NM_001406795.1:c.2395A>C
NM_001406796.1:c.2299A>C
NM_001406797.1:c.2002A>C
NM_001406798.1:c.2299A>C
NM_001406799.1:c.1774A>C
NM_001406800.1:c.2299A>C
NM_001406801.1:c.2002A>C
NM_001406802.1:c.2395A>C
NM_001406803.1:c.2299A>C
NM_001406804.1:c.2221A>C
NM_001406805.1:c.2002A>C
NM_001406806.1:c.1774A>C
NM_001406807.1:c.1774A>C
NM_001406808.1:c.2299A>C
NM_001406809.1:c.2299A>C
NM_001406811.1:c.1393A>C
NM_001406812.1:c.1393A>C
NM_001406813.1:c.2305A>C
NM_001406814.1:c.1393A>C
NM_001406815.1:c.1393A>C
NM_001406816.1:c.1393A>C
NM_001406818.1:c.2002A>C
NM_001406819.1:c.2002A>C
NM_001406820.1:c.2002A>C
NM_001406821.1:c.2002A>C
NM_001406822.1:c.2002A>C
NM_001406823.1:c.1393A>C
NM_001406824.1:c.2002A>C
NM_001406825.1:c.2002A>C
NM_001406826.1:c.2131A>C
NM_001406827.1:c.2002A>C
NM_001406828.1:c.2002A>C
NM_001406829.1:c.1393A>C
NM_001406830.1:c.2002A>C
NP_000170.1:p.Thr767Pro
NP_000170.1:p.Thr767Pro
NP_001268421.1:p.Thr637Pro
NP_001268422.1:p.Thr465Pro
NP_001268423.1:p.Thr465Pro
NP_001393724.1:p.Thr799Pro
NP_001393725.1:p.Thr767Pro
NP_001393726.1:p.Thr668Pro
NP_001393727.1:p.Thr767Pro
NP_001393728.1:p.Thr592Pro
NP_001393729.1:p.Thr767Pro
NP_001393730.1:p.Thr668Pro
NP_001393731.1:p.Thr799Pro
NP_001393732.1:p.Thr767Pro
NP_001393733.1:p.Thr741Pro
NP_001393734.1:p.Thr668Pro
NP_001393735.1:p.Thr592Pro
NP_001393736.1:p.Thr592Pro
NP_001393737.1:p.Thr767Pro
NP_001393738.1:p.Thr767Pro
NP_001393740.1:p.Thr465Pro
NP_001393741.1:p.Thr465Pro
NP_001393742.1:p.Thr769Pro
NP_001393743.1:p.Thr465Pro
NP_001393744.1:p.Thr465Pro
NP_001393745.1:p.Thr465Pro
NP_001393747.1:p.Thr668Pro
NP_001393748.1:p.Thr668Pro
NP_001393749.1:p.Thr668Pro
NP_001393750.1:p.Thr668Pro
NP_001393751.1:p.Thr668Pro
NP_001393752.1:p.Thr465Pro
NP_001393753.1:p.Thr668Pro
NP_001393754.1:p.Thr668Pro
NP_001393755.1:p.Thr711Pro
NP_001393756.1:p.Thr668Pro
NP_001393757.1:p.Thr668Pro
NP_001393758.1:p.Thr465Pro
NP_001393759.1:p.Thr668Pro
LRG_219t1:c.2299A>C
LRG_219:g.22136A>C
LRG_219p1:p.Thr767Pro
NC_000002.11:g.48027421A>C
NM_000179.2:c.2299A>C
NR_176256.1:n.1161A>C
NR_176257.1:n.2388A>C
NR_176258.1:n.2388A>C
NR_176259.1:n.2388A>C
NR_176261.1:n.2388A>C

Protein change:

T465P

Molecular consequence:

NM_000179.3:c.2299A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.1909A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.1393A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.1393A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406795.1:c.2395A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406796.1:c.2299A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406797.1:c.2002A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406798.1:c.2299A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406799.1:c.1774A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406800.1:c.2299A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406801.1:c.2002A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406802.1:c.2395A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406803.1:c.2299A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406804.1:c.2221A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406805.1:c.2002A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406806.1:c.1774A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406807.1:c.1774A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406808.1:c.2299A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406809.1:c.2299A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406811.1:c.1393A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406812.1:c.1393A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406813.1:c.2305A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406814.1:c.1393A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406815.1:c.1393A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406816.1:c.1393A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406818.1:c.2002A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406819.1:c.2002A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406820.1:c.2002A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406821.1:c.2002A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406822.1:c.2002A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406823.1:c.1393A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406824.1:c.2002A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406825.1:c.2002A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406826.1:c.2131A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406827.1:c.2002A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406828.1:c.2002A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406829.1:c.1393A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406830.1:c.2002A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003220847	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jul 22, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29755653, 31100584, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003220847

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jul 22, 2022)

germline

clinical testing

PubMed (3)
[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

TumorNext-Lynch-MMR: a comprehensive next generation sequencing assay for the detection of germline and somatic mutations in genes associated with mismatch repair deficiency and Lynch syndrome.

Gray PN, Tsai P, Chen D, Wu S, Hoo J, Mu W, Li B, Vuong H, Lu HM, Batth N, Willett S, Uyeda L, Shah S, Gau CL, Umali M, Espenschied C, Janicek M, Brown S, Margileth D, Dobrea L, Wagman L, Rana H, et al.

Oncotarget. 2018 Apr 17;9(29):20304-20322. doi: 10.18632/oncotarget.24854.

PubMed [citation]

PMID:: 29755653
PMCID:: PMC5945525

In-silico analysis of Thr767Ile pathogenic variant in the MSH6 gene in family with endometrial cancer.

Stembalska A, Klapecki J, Pławski A, Karpinski P.

Eur J Obstet Gynecol Reprod Biol. 2019 Jul;238:54-57. doi: 10.1016/j.ejogrb.2019.04.035. Epub 2019 Apr 22.

PubMed [citation]

PMID:: 31100584

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003220847.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 767 of the MSH6 protein (p.Thr767Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. 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 disrupts the p.Thr767 amino acid residue in MSH6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29755653, 31100584). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	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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