NM_000535.7(PMS2):c.2102A>G (p.His701Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 6, 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:: RCV002423095.2

Allele description [Variation Report for NM_000535.7(PMS2):c.2102A>G (p.His701Arg)]

NM_000535.7(PMS2):c.2102A>G (p.His701Arg)

Gene:

PMS2:PMS1 homolog 2, mismatch repair system component [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p22.1

Genomic location:

Preferred name:

NM_000535.7(PMS2):c.2102A>G (p.His701Arg)

HGVS:

NC_000007.14:g.5982896T>C
NG_008466.1:g.31211A>G
NM_000535.7:c.2102A>GMANE SELECT
NM_001322003.2:c.1697A>G
NM_001322004.2:c.1697A>G
NM_001322005.2:c.1697A>G
NM_001322006.2:c.1946A>G
NM_001322007.2:c.1784A>G
NM_001322008.2:c.1784A>G
NM_001322009.2:c.1697A>G
NM_001322010.2:c.1541A>G
NM_001322011.2:c.1169A>G
NM_001322012.2:c.1169A>G
NM_001322013.2:c.1529A>G
NM_001322014.2:c.2102A>G
NM_001322015.2:c.1793A>G
NP_000526.2:p.His701Arg
NP_001308932.1:p.His566Arg
NP_001308933.1:p.His566Arg
NP_001308934.1:p.His566Arg
NP_001308935.1:p.His649Arg
NP_001308936.1:p.His595Arg
NP_001308937.1:p.His595Arg
NP_001308938.1:p.His566Arg
NP_001308939.1:p.His514Arg
NP_001308940.1:p.His390Arg
NP_001308941.1:p.His390Arg
NP_001308942.1:p.His510Arg
NP_001308943.1:p.His701Arg
NP_001308944.1:p.His598Arg
LRG_161t1:c.2102A>G
LRG_161:g.31211A>G
NC_000007.13:g.6022527T>C
NM_000535.5:c.2102A>G
NR_136154.1:n.2189A>G

Protein change:

H390R

Links:

dbSNP: rs1583298873

NCBI 1000 Genomes Browser:

rs1583298873

Molecular consequence:

NM_000535.7:c.2102A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322003.2:c.1697A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322004.2:c.1697A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322005.2:c.1697A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.1946A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322007.2:c.1784A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322008.2:c.1784A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322009.2:c.1697A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322010.2:c.1541A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322011.2:c.1169A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322012.2:c.1169A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322013.2:c.1529A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.2102A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322015.2:c.1793A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.2189A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002724559	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (May 6, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23435383, 29755653 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002724559

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(May 6, 2022)

germline

clinical testing

PubMed (2)
[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

Citations

PubMed

Structure of the MutLα C-terminal domain reveals how Mlh1 contributes to Pms1 endonuclease site.

Gueneau E, Dherin C, Legrand P, Tellier-Lebegue C, Gilquin B, Bonnesoeur P, Londino F, Quemener C, Le Du MH, Márquez JA, Moutiez M, Gondry M, Boiteux S, Charbonnier JB.

Nat Struct Mol Biol. 2013 Apr;20(4):461-8. doi: 10.1038/nsmb.2511. Epub 2013 Feb 24.

PubMed [citation]

PMID:: 23435383

TumorNext-Lynch-MMR: a comprehensive next generation sequencing assay for the detection of germline and somatic mutations in genes associated with mismatch repair deficiency and Lynch syndrome.

Gray PN, Tsai P, Chen D, Wu S, Hoo J, Mu W, Li B, Vuong H, Lu HM, Batth N, Willett S, Uyeda L, Shah S, Gau CL, Umali M, Espenschied C, Janicek M, Brown S, Margileth D, Dobrea L, Wagman L, Rana H, et al.

Oncotarget. 2018 Apr 17;9(29):20304-20322. doi: 10.18632/oncotarget.24854.

PubMed [citation]

PMID:: 29755653
PMCID:: PMC5945525

Details of each submission

From Ambry Genetics, SCV002724559.2

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

Description

The p.H701R variant (also known as c.2102A>G), located in coding exon 12 of the PMS2 gene, results from an A to G substitution at nucleotide position 2102. The histidine at codon 701 is replaced by arginine, an amino acid with highly similar properties. This alteration was identified in an individual with colon cancer and a strong family history of HNPCC-related cancers. Tumor results for this individual revealed microsatellite instability and loss of PMS2 protein on immunohistochemistry (Ambry internal data). Based on internal structural analysis, this variant sits at the interface between PMS2/MutLa and is anticipated to result in a significant decrease in structural stability (Gueneau E et al. Nat. Struct. Mol. Biol. 2013 Apr;20(4):461-8). This amino acid position is highly conserved in available vertebrate species. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). In addition, this alteration 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.

#	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

ClinVar

Relating variation to medicine