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NM_000179.3(MSH6):c.3646G>A (p.Gly1216Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
May 26, 2022
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:
RCV000491503.4

Allele description [Variation Report for NM_000179.3(MSH6):c.3646G>A (p.Gly1216Arg)]

NM_000179.3(MSH6):c.3646G>A (p.Gly1216Arg)

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.3646G>A (p.Gly1216Arg)
HGVS:
  • NC_000002.12:g.47805707G>A
  • NG_007111.1:g.27561G>A
  • NG_008397.1:g.104969C>T
  • NM_000179.3:c.3646G>AMANE SELECT
  • NM_001281492.2:c.3256G>A
  • NM_001281493.2:c.2740G>A
  • NM_001281494.2:c.2740G>A
  • NP_000170.1:p.Gly1216Arg
  • NP_000170.1:p.Gly1216Arg
  • NP_001268421.1:p.Gly1086Arg
  • NP_001268422.1:p.Gly914Arg
  • NP_001268423.1:p.Gly914Arg
  • LRG_219t1:c.3646G>A
  • LRG_219:g.27561G>A
  • LRG_219p1:p.Gly1216Arg
  • NC_000002.11:g.48032846G>A
  • NM_000179.2:c.3646G>A
Protein change:
G1086R
Links:
dbSNP: rs1114167690
NCBI 1000 Genomes Browser:
rs1114167690
Molecular consequence:
  • NM_000179.3:c.3646G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281492.2:c.3256G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281493.2:c.2740G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281494.2:c.2740G>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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000580097Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(May 26, 2022) 		germlineclinical testing

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

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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, SCV000580097.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

The p.G1216R variant (also known as c.3646G>A), located in coding exon 7 of the MSH6 gene, results from a G to A substitution at nucleotide position 3646. The amino acid change results in glycine to arginine at codon 1216, an amino acid with dissimilar properties. However, this change occurs in the last base pair of coding exon 7 and may have some effect on normal mRNA splicing. Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Warren JJ et al. Mol. Cell. 2007 May;26:579-92; Ambry internal data). This variant co-segregated with Lynch-associated cancers in multiple families (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. This amino acid position is highly conserved in available vertebrate species. In addition, as a missense substitution this is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 1, 2024