NM_000179.3(MSH6):c.3517G>A (p.Val1173Met) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Sep 26, 2023
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:: RCV000573393.11

Allele description [Variation Report for NM_000179.3(MSH6):c.3517G>A (p.Val1173Met)]

NM_000179.3(MSH6):c.3517G>A (p.Val1173Met)

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.3517G>A (p.Val1173Met)

Other names:

p.V1173M:GTG>ATG

HGVS:

NC_000002.12:g.47804988G>A
NG_007111.1:g.26842G>A
NG_008397.1:g.105688C>T
NM_000179.3:c.3517G>AMANE SELECT
NM_001281492.2:c.3127G>A
NM_001281493.2:c.2611G>A
NM_001281494.2:c.2611G>A
NP_000170.1:p.Val1173Met
NP_000170.1:p.Val1173Met
NP_001268421.1:p.Val1043Met
NP_001268422.1:p.Val871Met
NP_001268423.1:p.Val871Met
LRG_219t1:c.3517G>A
LRG_219:g.26842G>A
LRG_219p1:p.Val1173Met
NC_000002.11:g.48032127G>A
NM_000179.2:c.3517G>A

Protein change:

V1043M

Links:

dbSNP: rs730881806

NCBI 1000 Genomes Browser:

rs730881806

Molecular consequence:

NM_000179.3:c.3517G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.3127G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.2611G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.2611G>A - 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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coq8 ABC1 kinase family ubiquinone biosynthesis ATPase Coq8 [Schizosaccharomyces...
coq8 ABC1 kinase family ubiquinone biosynthesis ATPase Coq8 [Schizosaccharomyces pombe]
Gene ID:2540411

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000662384	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Apr 27, 2023)	germline	clinical testing	Citation Link,
SCV000685412	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 13, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004228133	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 26, 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

SCV000662384

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Apr 27, 2023)

germline

clinical testing

Citation Link,

SCV000685412

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 13, 2023)

germline

clinical testing

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

SCV004228133

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 26, 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

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

Details of each submission

From Ambry Genetics, SCV000662384.6

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

Description

The p.V1173M variant (also known as c.3517G>A), located in coding exon 6 of the MSH6 gene, results from a G to A substitution at nucleotide position 3517. The valine at codon 1173 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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, SCV000685412.5

#	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 valine with methionine at codon 1173 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 1/251294 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 Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C., SCV004228133.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	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 29, 2024

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