NM_000179.3(MSH6):c.956C>T (p.Thr319Met) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 21, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000656996.10

Allele description [Variation Report for NM_000179.3(MSH6):c.956C>T (p.Thr319Met)]

NM_000179.3(MSH6):c.956C>T (p.Thr319Met)

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.956C>T (p.Thr319Met)

HGVS:

NC_000002.12:g.47798939C>T
NG_007111.1:g.20793C>T
NM_000179.3:c.956C>TMANE SELECT
NM_001281492.2:c.566C>T
NM_001281493.2:c.50C>T
NM_001281494.2:c.50C>T
NP_000170.1:p.Thr319Met
NP_000170.1:p.Thr319Met
NP_001268421.1:p.Thr189Met
NP_001268422.1:p.Thr17Met
NP_001268423.1:p.Thr17Met
LRG_219t1:c.956C>T
LRG_219:g.20793C>T
LRG_219p1:p.Thr319Met
NC_000002.11:g.48026078C>T
NM_000179.2:c.956C>T

Protein change:

T17M

Links:

dbSNP: rs188252826

NCBI 1000 Genomes Browser:

rs188252826

Molecular consequence:

NM_000179.3:c.956C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.566C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.50C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.50C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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collapsin response mediator protein 4A, partial [Mus musculus]
collapsin response mediator protein 4A, partial [Mus musculus]
gi|33323447|gb|AAQ07444.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000601623	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (May 21, 2021)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23621914, 26467025
SCV000616946	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Dec 4, 2017)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000601623

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(May 21, 2021)

unknown

clinical testing

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

SCV000616946

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Dec 4, 2017)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

CoDP: predicting the impact of unclassified genetic variants in MSH6 by the combination of different properties of the protein.

Terui H, Akagi K, Kawame H, Yura K.

J Biomed Sci. 2013 Apr 28;20:25. doi: 10.1186/1423-0127-20-25.

PubMed [citation]

PMID:: 23621914
PMCID:: PMC3651391

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

Details of each submission

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000601623.2

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV000616946.3

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

Description

This variant is denoted MSH6 c.956C>T at the cDNA level, p.Thr319Met (T319M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Thr319Met was not observed in large population cohorts (Lek 2016). Since Threonine and Methionine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Thr319Met is located within the nuclear localization signals (Gassman 2011). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether MSH6 Thr319Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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