NM_000179.3(MSH6):c.818G>T (p.Gly273Val) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Feb 20, 2024
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:: RCV000561246.12

Allele description [Variation Report for NM_000179.3(MSH6):c.818G>T (p.Gly273Val)]

NM_000179.3(MSH6):c.818G>T (p.Gly273Val)

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.818G>T (p.Gly273Val)

HGVS:

NC_000002.12:g.47798801G>T
NG_007111.1:g.20655G>T
NM_000179.3:c.818G>TMANE SELECT
NM_001281492.2:c.428G>T
NM_001281493.2:c.-89G>T
NM_001281494.2:c.-89G>T
NP_000170.1:p.Gly273Val
NP_000170.1:p.Gly273Val
NP_001268421.1:p.Gly143Val
LRG_219t1:c.818G>T
LRG_219:g.20655G>T
LRG_219p1:p.Gly273Val
NC_000002.11:g.48025940G>T
NM_000179.2:c.818G>T

Protein change:

G143V

Links:

dbSNP: rs769610487

NCBI 1000 Genomes Browser:

rs769610487

Molecular consequence:

NM_001281493.2:c.-89G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001281494.2:c.-89G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000179.3:c.818G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.428G>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
SCV000669949	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Feb 20, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000685521	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 18, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002536355	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (May 4, 2021)	germline	curation	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

SCV000669949

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Feb 20, 2024)

germline

clinical testing

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

Citation Link,

SCV000685521

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 18, 2021)

germline

clinical testing

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

SCV002536355

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(May 4, 2021)

germline

curation

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, curation

Citations

PubMed

Clinical Testing for Mismatch Repair in Neoplasms Using Multiple Laboratory Methods.

Yang RK, Chen H, Roy-Chowdhuri S, Rashid A, Alvarez H, Routbort M, Patel KP, Luthra R, Medeiros LJ, Toruner GA.

Cancers (Basel). 2022 Sep 20;14(19). doi:pii: 4550. 10.3390/cancers14194550.

PubMed [citation]

PMID:: 36230473
PMCID:: PMC9559284

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000669949.6

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

Description

The p.G273V variant (also known as c.818G>T), located in coding exon 4 of the MSH6 gene, results from a G to T substitution at nucleotide position 818. The glycine at codon 273 is replaced by valine, an amino acid with dissimilar properties. This variant has been identified in a proband whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and normal mismatch repair expression by immunohistochemistry (Yang RK et al. Cancers (Basel), 2022 Sep;14). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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

From Color Diagnostics, LLC DBA Color Health, SCV000685521.4

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

Description

This missense variant replaces glycine with valine at codon 273 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251030 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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

From Sema4, Sema4, SCV002536355.1

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

#	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 16, 2024

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