NM_000179.3(MSH6):c.2408A>G (p.Asp803Gly) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Feb 1, 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:: RCV000130124.19

Allele description [Variation Report for NM_000179.3(MSH6):c.2408A>G (p.Asp803Gly)]

NM_000179.3(MSH6):c.2408A>G (p.Asp803Gly)

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.2408A>G (p.Asp803Gly)

Other names:

p.D803G:GAC>GGC

HGVS:

NC_000002.12:g.47800391A>G
NG_007111.1:g.22245A>G
NM_000179.3:c.2408A>GMANE SELECT
NM_001281492.2:c.2018A>G
NM_001281493.2:c.1502A>G
NM_001281494.2:c.1502A>G
NP_000170.1:p.Asp803Gly
NP_000170.1:p.Asp803Gly
NP_001268421.1:p.Asp673Gly
NP_001268422.1:p.Asp501Gly
NP_001268423.1:p.Asp501Gly
LRG_219t1:c.2408A>G
LRG_219:g.22245A>G
LRG_219p1:p.Asp803Gly
NC_000002.11:g.48027530A>G
NM_000179.2:c.2408A>G
P52701:p.Asp803Gly
p.D803G

Protein change:

D501G

Links:

UniProtKB: P52701#VAR_012962; dbSNP: rs63751450

NCBI 1000 Genomes Browser:

rs63751450

Molecular consequence:

NM_000179.3:c.2408A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.2018A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.1502A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.1502A>G - 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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Homo sapiens uncharacterized LOC100507634 (LOC100507634), long non-coding RNA
Homo sapiens uncharacterized LOC100507634 (LOC100507634), long non-coding RNA
gi|334085261|ref|NR_038320.1|

Nucleotide
Iris,Dorsal,4dpl,Rep2 [D4_Dorsal_2]
Iris,Dorsal,4dpl,Rep2 [D4_Dorsal_2]

biosample
Bacteroides intestinalis isolate:Bacteroides intestinalis TSDC20.2-1.2
Bacteroides intestinalis isolate:Bacteroides intestinalis TSDC20.2-1.2
Strain Bacteroides intestinalis TSDC20.2-1.2 (species Bacteroides intestinalis) was isolated from the fecal microbiota of a USA female at time point zero (bacterial isolates were sequenced from this donor on day 0 and 57). The species name was assigned by genome clustering.

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000184956	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Feb 1, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10537275, 18790734, 23621914, 25637381, 28944238 Citation Link,
SCV000537593	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 20, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 10537275, 18790734, 25186627, 25479140, 26689913, 31391288, 31428572, 33471991, 25741868
SCV002535734	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Oct 11, 2021)	germline	curation	PubMed (7) [See all records that cite these PMIDs] 10537275, 25479140, 25186627, 26689913, 31428572, 33471991, 18790734 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000184956

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Feb 1, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV000537593

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 20, 2023)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV002535734

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Oct 11, 2021)

germline

curation

PubMed (7)
[See all records that cite these PMIDs]

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, curation

Citations

PubMed

CoDP: predicting the impact of unclassified genetic variants in MSH6 by the combination of different properties of the protein.

Terui H, Akagi K, Kawame H, Yura K.

J Biomed Sci. 2013 Apr 28;20:25. doi: 10.1186/1423-0127-20-25.

PubMed [citation]

PMID:: 23621914
PMCID:: PMC3651391

Actionable exomic incidental findings in 6503 participants: challenges of variant classification.

Amendola LM, Dorschner MO, Robertson PD, Salama JS, Hart R, Shirts BH, Murray ML, Tokita MJ, Gallego CJ, Kim DS, Bennett JT, Crosslin DR, Ranchalis J, Jones KL, Rosenthal EA, Jarvik ER, Itsara A, Turner EH, Herman DS, Schleit J, Burt A, Jamal SM, et al.

Genome Res. 2015 Mar;25(3):305-15. doi: 10.1101/gr.183483.114. Epub 2015 Jan 30.

PubMed [citation]

PMID:: 25637381
PMCID:: PMC4352885

See all PubMed Citations (12)

Details of each submission

From Ambry Genetics, SCV000184956.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The p.D803G variant (also known as c.2408A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 2408. The aspartic acid at codon 803 is replaced by glycine, an amino acid with similar properties. This variant was first reported in a familial CRC kindred and has been shown to reduce the ATP-binding potential of MSH6 (Kolodner RD et al. Cancer Res. 1999 Oct;59:5068-74; Cyr JL and Heinen CD. J. Biol. Chem. 2008 Nov;283:31641-8). This alteration was also identified in an individual diagnosed with colorectal cancer (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, 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, SCV000537593.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This missense variant replaces aspartic acid with glycine at codon 803 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has reported that this variant protein has reduced nucleotide exchange and ATPase activities (PMID: 18790734). This variant has been reported in individuals affected with colorectal, breast, pancreatic cancer or glioblastoma multiforme (PMID: 10537275, 25186627, 25479140, 26689913, 31391288, 31428572, 33471991), as well as in several healthy controls in a breast cancer case-control study (PMID: 33471991). This variant has been identified in 22/282092 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 Sema4, Sema4, SCV002535734.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (7)

#	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: Nov 10, 2024

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