NM_000179.3(MSH6):c.2054G>A (p.Gly685Asp) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 27, 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:: RCV002421860.2

Allele description [Variation Report for NM_000179.3(MSH6):c.2054G>A (p.Gly685Asp)]

NM_000179.3(MSH6):c.2054G>A (p.Gly685Asp)

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.2054G>A (p.Gly685Asp)

HGVS:

NC_000002.12:g.47800037G>A
NG_007111.1:g.21891G>A
NM_000179.3:c.2054G>AMANE SELECT
NM_001281492.2:c.1664G>A
NM_001281493.2:c.1148G>A
NM_001281494.2:c.1148G>A
NM_001406795.1:c.2150G>A
NM_001406796.1:c.2054G>A
NM_001406797.1:c.1757G>A
NM_001406798.1:c.2054G>A
NM_001406799.1:c.1529G>A
NM_001406800.1:c.2054G>A
NM_001406801.1:c.1757G>A
NM_001406802.1:c.2150G>A
NM_001406803.1:c.2054G>A
NM_001406804.1:c.1976G>A
NM_001406805.1:c.1757G>A
NM_001406806.1:c.1529G>A
NM_001406807.1:c.1529G>A
NM_001406808.1:c.2054G>A
NM_001406809.1:c.2054G>A
NM_001406811.1:c.1148G>A
NM_001406812.1:c.1148G>A
NM_001406813.1:c.2060G>A
NM_001406814.1:c.1148G>A
NM_001406815.1:c.1148G>A
NM_001406816.1:c.1148G>A
NM_001406818.1:c.1757G>A
NM_001406819.1:c.1757G>A
NM_001406820.1:c.1757G>A
NM_001406821.1:c.1757G>A
NM_001406822.1:c.1757G>A
NM_001406823.1:c.1148G>A
NM_001406824.1:c.1757G>A
NM_001406825.1:c.1757G>A
NM_001406826.1:c.1886G>A
NM_001406827.1:c.1757G>A
NM_001406828.1:c.1757G>A
NM_001406829.1:c.1148G>A
NM_001406830.1:c.1757G>A
NP_000170.1:p.Gly685Asp
NP_000170.1:p.Gly685Asp
NP_001268421.1:p.Gly555Asp
NP_001268422.1:p.Gly383Asp
NP_001268423.1:p.Gly383Asp
NP_001393724.1:p.Gly717Asp
NP_001393725.1:p.Gly685Asp
NP_001393726.1:p.Gly586Asp
NP_001393727.1:p.Gly685Asp
NP_001393728.1:p.Gly510Asp
NP_001393729.1:p.Gly685Asp
NP_001393730.1:p.Gly586Asp
NP_001393731.1:p.Gly717Asp
NP_001393732.1:p.Gly685Asp
NP_001393733.1:p.Gly659Asp
NP_001393734.1:p.Gly586Asp
NP_001393735.1:p.Gly510Asp
NP_001393736.1:p.Gly510Asp
NP_001393737.1:p.Gly685Asp
NP_001393738.1:p.Gly685Asp
NP_001393740.1:p.Gly383Asp
NP_001393741.1:p.Gly383Asp
NP_001393742.1:p.Gly687Asp
NP_001393743.1:p.Gly383Asp
NP_001393744.1:p.Gly383Asp
NP_001393745.1:p.Gly383Asp
NP_001393747.1:p.Gly586Asp
NP_001393748.1:p.Gly586Asp
NP_001393749.1:p.Gly586Asp
NP_001393750.1:p.Gly586Asp
NP_001393751.1:p.Gly586Asp
NP_001393752.1:p.Gly383Asp
NP_001393753.1:p.Gly586Asp
NP_001393754.1:p.Gly586Asp
NP_001393755.1:p.Gly629Asp
NP_001393756.1:p.Gly586Asp
NP_001393757.1:p.Gly586Asp
NP_001393758.1:p.Gly383Asp
NP_001393759.1:p.Gly586Asp
LRG_219t1:c.2054G>A
LRG_219:g.21891G>A
LRG_219p1:p.Gly685Asp
NC_000002.11:g.48027176G>A
NM_000179.2:c.2054G>A
NR_176256.1:n.916G>A
NR_176257.1:n.2143G>A
NR_176258.1:n.2143G>A
NR_176259.1:n.2143G>A
NR_176261.1:n.2143G>A

Protein change:

G383D

Molecular consequence:

NM_000179.3:c.2054G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.1664G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.1148G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.1148G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406795.1:c.2150G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406796.1:c.2054G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406797.1:c.1757G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406798.1:c.2054G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406799.1:c.1529G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406800.1:c.2054G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406801.1:c.1757G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406802.1:c.2150G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406803.1:c.2054G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406804.1:c.1976G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406805.1:c.1757G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406806.1:c.1529G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406807.1:c.1529G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406808.1:c.2054G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406809.1:c.2054G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406811.1:c.1148G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406812.1:c.1148G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406813.1:c.2060G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406814.1:c.1148G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406815.1:c.1148G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406816.1:c.1148G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406818.1:c.1757G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406819.1:c.1757G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406820.1:c.1757G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406821.1:c.1757G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406822.1:c.1757G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406823.1:c.1148G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406824.1:c.1757G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406825.1:c.1757G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406826.1:c.1886G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406827.1:c.1757G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406828.1:c.1757G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406829.1:c.1148G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406830.1:c.1757G>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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Homo sapiens tolloid like 1 (TLL1), transcript variant 1, mRNA
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Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002725548	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Dec 27, 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

SCV002725548

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Dec 27, 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

Structure of the human MutSalpha DNA lesion recognition complex.

Warren JJ, Pohlhaus TJ, Changela A, Iyer RR, Modrich PL, Beese LS.

Mol Cell. 2007 May 25;26(4):579-92.

PubMed [citation]

PMID:: 17531815

Details of each submission

From Ambry Genetics, SCV002725548.2

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

Description

The p.G685D variant (also known as c.2054G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 2054. The glycine at codon 685 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been observed in at least one individual who has a personal or family history that is consistent with MSH6-associated disease (Ambry internal data). Based on internal structural assessment, this alteration significantly destabilizes the connector domain of the MSH6 protein (Warren JJ et al. Mol. Cell, 2007 May;26:579-92). 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 likely impair molecular function, with a score of 0.998 (Terui H et al. J. Biomed. Sci. 2013;20:25). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#	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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