NM_000179.3(MSH6):c.2342C>T (p.Pro781Leu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 17, 2024
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:: RCV004023356.1

Allele description [Variation Report for NM_000179.3(MSH6):c.2342C>T (p.Pro781Leu)]

NM_000179.3(MSH6):c.2342C>T (p.Pro781Leu)

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.2342C>T (p.Pro781Leu)

HGVS:

NC_000002.12:g.47800325C>T
NG_007111.1:g.22179C>T
NM_000179.3:c.2342C>TMANE SELECT
NM_001281492.2:c.1952C>T
NM_001281493.2:c.1436C>T
NM_001281494.2:c.1436C>T
NP_000170.1:p.Pro781Leu
NP_000170.1:p.Pro781Leu
NP_001268421.1:p.Pro651Leu
NP_001268422.1:p.Pro479Leu
NP_001268423.1:p.Pro479Leu
LRG_219t1:c.2342C>T
LRG_219:g.22179C>T
LRG_219p1:p.Pro781Leu
NC_000002.11:g.48027464C>T
NM_000179.2:c.2342C>T

Protein change:

P479L

Links:

dbSNP: rs1553413710

NCBI 1000 Genomes Browser:

rs1553413710

Molecular consequence:

NM_000179.3:c.2342C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.1952C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.1436C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.1436C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV005032832	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Jan 17, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV005032832

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Jan 17, 2024)

germline

clinical testing

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

Citation Link

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

Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance.

Tsai GJ, Rañola JMO, Smith C, Garrett LT, Bergquist T, Casadei S, Bowen DJ, Shirts BH.

Genet Med. 2019 Jun;21(6):1435-1442. doi: 10.1038/s41436-018-0335-7. Epub 2018 Oct 30.

PubMed [citation]

PMID:: 30374176

Details of each submission

From Ambry Genetics, SCV005032832.1

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

Description

The p.P781L variant (also known as c.2342C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 2342. The proline at codon 781 is replaced by leucine, an amino acid with similar properties. This alteration was detected in a proband whose tumor showed high microsatellite instability (MSI-H) and loss of MSH6 by immunohistochemistry (IHC), and was classified as pathogenic by a study that evaluated multiple lines of evidence, including population data, functional evidence, in silico prediction models, segregation with disease and clinical phenotype including tumor characteristics (Tsai GJ et al. Genet Med, 2019 Jun;21:1435-1442). Another alteration at the same codon, p.P781S (c.2341C>T), has been identified in multiple individuals whose tumors were MSI-H and demonstrated loss of MSH6 protein expression by IHC (Buchanan DD et al. J. Gastroenterol. Hepatol., 2017 Feb;32:427-438; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be 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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