NM_000179.3(MSH6):c.1430G>A (p.Gly477Asp) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 28, 2018
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:: RCV002392062.2

Allele description [Variation Report for NM_000179.3(MSH6):c.1430G>A (p.Gly477Asp)]

NM_000179.3(MSH6):c.1430G>A (p.Gly477Asp)

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.1430G>A (p.Gly477Asp)

HGVS:

NC_000002.12:g.47799413G>A
NG_007111.1:g.21267G>A
NM_000179.3:c.1430G>AMANE SELECT
NM_001281492.2:c.1040G>A
NM_001281493.2:c.524G>A
NM_001281494.2:c.524G>A
NM_001406795.1:c.1526G>A
NM_001406796.1:c.1430G>A
NM_001406797.1:c.1133G>A
NM_001406798.1:c.1430G>A
NM_001406799.1:c.905G>A
NM_001406800.1:c.1430G>A
NM_001406801.1:c.1133G>A
NM_001406802.1:c.1526G>A
NM_001406803.1:c.1430G>A
NM_001406804.1:c.1352G>A
NM_001406805.1:c.1133G>A
NM_001406806.1:c.905G>A
NM_001406807.1:c.905G>A
NM_001406808.1:c.1430G>A
NM_001406809.1:c.1430G>A
NM_001406811.1:c.524G>A
NM_001406812.1:c.524G>A
NM_001406813.1:c.1436G>A
NM_001406814.1:c.524G>A
NM_001406815.1:c.524G>A
NM_001406816.1:c.524G>A
NM_001406817.1:c.1430G>A
NM_001406818.1:c.1133G>A
NM_001406819.1:c.1133G>A
NM_001406820.1:c.1133G>A
NM_001406821.1:c.1133G>A
NM_001406822.1:c.1133G>A
NM_001406823.1:c.524G>A
NM_001406824.1:c.1133G>A
NM_001406825.1:c.1133G>A
NM_001406826.1:c.1262G>A
NM_001406827.1:c.1133G>A
NM_001406828.1:c.1133G>A
NM_001406829.1:c.524G>A
NM_001406830.1:c.1133G>A
NP_000170.1:p.Gly477Asp
NP_000170.1:p.Gly477Asp
NP_001268421.1:p.Gly347Asp
NP_001268422.1:p.Gly175Asp
NP_001268423.1:p.Gly175Asp
NP_001393724.1:p.Gly509Asp
NP_001393725.1:p.Gly477Asp
NP_001393726.1:p.Gly378Asp
NP_001393727.1:p.Gly477Asp
NP_001393728.1:p.Gly302Asp
NP_001393729.1:p.Gly477Asp
NP_001393730.1:p.Gly378Asp
NP_001393731.1:p.Gly509Asp
NP_001393732.1:p.Gly477Asp
NP_001393733.1:p.Gly451Asp
NP_001393734.1:p.Gly378Asp
NP_001393735.1:p.Gly302Asp
NP_001393736.1:p.Gly302Asp
NP_001393737.1:p.Gly477Asp
NP_001393738.1:p.Gly477Asp
NP_001393740.1:p.Gly175Asp
NP_001393741.1:p.Gly175Asp
NP_001393742.1:p.Gly479Asp
NP_001393743.1:p.Gly175Asp
NP_001393744.1:p.Gly175Asp
NP_001393745.1:p.Gly175Asp
NP_001393746.1:p.Gly477Asp
NP_001393747.1:p.Gly378Asp
NP_001393748.1:p.Gly378Asp
NP_001393749.1:p.Gly378Asp
NP_001393750.1:p.Gly378Asp
NP_001393751.1:p.Gly378Asp
NP_001393752.1:p.Gly175Asp
NP_001393753.1:p.Gly378Asp
NP_001393754.1:p.Gly378Asp
NP_001393755.1:p.Gly421Asp
NP_001393756.1:p.Gly378Asp
NP_001393757.1:p.Gly378Asp
NP_001393758.1:p.Gly175Asp
NP_001393759.1:p.Gly378Asp
LRG_219t1:c.1430G>A
LRG_219:g.21267G>A
LRG_219p1:p.Gly477Asp
NC_000002.11:g.48026552G>A
NM_000179.2:c.1430G>A
NR_176257.1:n.1519G>A
NR_176258.1:n.1519G>A
NR_176259.1:n.1519G>A
NR_176261.1:n.1519G>A

Protein change:

G175D

Molecular consequence:

NM_000179.3:c.1430G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.1040G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.524G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.524G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406795.1:c.1526G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406796.1:c.1430G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406797.1:c.1133G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406798.1:c.1430G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406799.1:c.905G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406800.1:c.1430G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406801.1:c.1133G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406802.1:c.1526G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406803.1:c.1430G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406804.1:c.1352G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406805.1:c.1133G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406806.1:c.905G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406807.1:c.905G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406808.1:c.1430G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406809.1:c.1430G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406811.1:c.524G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406812.1:c.524G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406813.1:c.1436G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406814.1:c.524G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406815.1:c.524G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406816.1:c.524G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406817.1:c.1430G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406818.1:c.1133G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406819.1:c.1133G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406820.1:c.1133G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406821.1:c.1133G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406822.1:c.1133G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406823.1:c.524G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406824.1:c.1133G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406825.1:c.1133G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406826.1:c.1262G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406827.1:c.1133G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406828.1:c.1133G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406829.1:c.524G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406830.1:c.1133G>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002698507	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Aug 28, 2018)	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

SCV002698507

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Aug 28, 2018)

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

Functional analysis of human mismatch repair gene mutations identifies weak alleles and polymorphisms capable of polygenic interactions.

Martinez SL, Kolodner RD.

Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):5070-5. doi: 10.1073/pnas.1000798107. Epub 2010 Feb 22.

PubMed [citation]

PMID:: 20176959
PMCID:: PMC2841877

Details of each submission

From Ambry Genetics, SCV002698507.2

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

Description

The p.G477D variant (also known as c.1430G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 1430. The glycine at codon 477 is replaced by aspartic acid, an amino acid with similar properties. In a functional assay measuring mutation rates in yeast, the yeast equivalent of this alteration alone had little effect on mismatch repair (MMR) activity and was similar to wild type MSH6; however, a double mutant consisting of this alteration along with a weak allele in MSH2 synergistically showed a reduction in MMR activity (Martinez SL et al. Proc. Natl. Acad. Sci. U.S.A., 2010 Mar;107:5070-5). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, the CoDP in silico tool predicts this alteration to have a likely impact on molecular function, with a score of 0.952 (Terui H et al. J. Biomed. Sci. 2013 Apr;20:25). 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

Last Updated: May 1, 2024

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