NM_000179.3(MSH6):c.2315G>A (p.Arg772Gln) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 6, 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:: RCV001015160.10

Allele description [Variation Report for NM_000179.3(MSH6):c.2315G>A (p.Arg772Gln)]

NM_000179.3(MSH6):c.2315G>A (p.Arg772Gln)

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.2315G>A (p.Arg772Gln)

HGVS:

NC_000002.12:g.47800298G>A
NG_007111.1:g.22152G>A
NM_000179.3:c.2315G>AMANE SELECT
NM_001281492.2:c.1925G>A
NM_001281493.2:c.1409G>A
NM_001281494.2:c.1409G>A
NP_000170.1:p.Arg772Gln
NP_000170.1:p.Arg772Gln
NP_001268421.1:p.Arg642Gln
NP_001268422.1:p.Arg470Gln
NP_001268423.1:p.Arg470Gln
LRG_219t1:c.2315G>A
LRG_219:g.22152G>A
LRG_219p1:p.Arg772Gln
NC_000002.11:g.48027437G>A
NM_000179.2:c.2315G>A
P52701:p.Arg772Gln

Protein change:

R470Q

Links:

UniProtKB: P52701#VAR_043957; dbSNP: rs63750725

NCBI 1000 Genomes Browser:

rs63750725

Molecular consequence:

NM_000179.3:c.2315G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.1925G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.1409G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.1409G>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

Recent activity

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enoyl-CoA hydratase/isomerase family protein [Desulfobacula toluolica]
enoyl-CoA hydratase/isomerase family protein [Desulfobacula toluolica]
gi|504772058|ref|WP_014959160.1|

Protein
uncharacterized protein LOC111446882 isoform X1 [Cucurbita moschata]
uncharacterized protein LOC111446882 isoform X1 [Cucurbita moschata]
gi|1279754736|ref|XP_022941569.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001175967	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (May 6, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001354859	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 2, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25985138, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001175967

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(May 6, 2024)

germline

clinical testing

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

Citation Link,

SCV001354859

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 2, 2023)

germline

clinical testing

PubMed (2)
[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

Using Somatic Mutations from Tumors to Classify Variants in Mismatch Repair Genes.

Shirts BH, Konnick EQ, Upham S, Walsh T, Ranola JMO, Jacobson AL, King MC, Pearlman R, Hampel H, Pritchard CC.

Am J Hum Genet. 2018 Jul 5;103(1):19-29. doi: 10.1016/j.ajhg.2018.05.001. Epub 2018 Jun 7.

PubMed [citation]

PMID:: 29887214
PMCID:: PMC6035155

Factors influencing success of clinical genome sequencing across a broad spectrum of disorders.

Taylor JC, Martin HC, Lise S, Broxholme J, Cazier JB, Rimmer A, Kanapin A, Lunter G, Fiddy S, Allan C, Aricescu AR, Attar M, Babbs C, Becq J, Beeson D, Bento C, Bignell P, Blair E, Buckle VJ, Bull K, Cais O, Cario H, et al.

Nat Genet. 2015 Jul;47(7):717-726. doi: 10.1038/ng.3304. Epub 2015 May 18.

PubMed [citation]

PMID:: 25985138
PMCID:: PMC4601524

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV001175967.6

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

Description

The p.R772Q variant (also known as c.2315G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 2315. The arginine at codon 772 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been detected in conjunction with a pathogenic MSH6 mutation (phase unknown) in an individual with an unspecified number of multiple adenomas (Taylor JC et al. Nat Genet. 2015 Jul;47(7):717-26). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant 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, SCV001354859.3

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

Description

This missense variant replaces arginine with glutamine at codon 772 of the MSH6 protein. A different variant affecting the same position c.2314C>T (p.Arg772Trp) is considered to be disease-causing (ClinVar variation ID: 89267). 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 performed for this variant. This variant has been reported in an individual with multiple adenomas who also had a MSH6 nonsense mutation (PMID: 25985138). This variant has been identified in 5/282522 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.2314C>T (p.Arg772Trp), is considered to be disease-causing (ClinVar variation ID: 89267), suggesting that this position is important for the protein function. 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

Last Updated: Sep 29, 2024

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