NM_000535.7(PMS2):c.506G>A (p.Arg169His) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 15, 2023
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:: RCV000215633.11

Allele description [Variation Report for NM_000535.7(PMS2):c.506G>A (p.Arg169His)]

NM_000535.7(PMS2):c.506G>A (p.Arg169His)

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.506G>A (p.Arg169His)

Other names:

p.R169H:CGC>CAC

HGVS:

NC_000007.14:g.6002484C>T
NG_008466.1:g.11623G>A
NM_000535.7:c.506G>AMANE SELECT
NM_001322003.2:c.101G>A
NM_001322004.2:c.101G>A
NM_001322005.2:c.101G>A
NM_001322006.2:c.506G>A
NM_001322007.2:c.188G>A
NM_001322008.2:c.188G>A
NM_001322009.2:c.101G>A
NM_001322010.2:c.101G>A
NM_001322011.2:c.-379G>A
NM_001322012.2:c.-379G>A
NM_001322013.2:c.101G>A
NM_001322014.2:c.506G>A
NM_001322015.2:c.197G>A
NP_000526.2:p.Arg169His
NP_001308932.1:p.Arg34His
NP_001308933.1:p.Arg34His
NP_001308934.1:p.Arg34His
NP_001308935.1:p.Arg169His
NP_001308936.1:p.Arg63His
NP_001308937.1:p.Arg63His
NP_001308938.1:p.Arg34His
NP_001308939.1:p.Arg34His
NP_001308942.1:p.Arg34His
NP_001308943.1:p.Arg169His
NP_001308944.1:p.Arg66His
LRG_161t1:c.506G>A
LRG_161:g.11623G>A
NC_000007.13:g.6042115C>T
NM_000535.5:c.506G>A
NM_000535.6:c.506G>A
NR_136154.1:n.593G>A

Protein change:

R169H

Links:

dbSNP: rs730881917

NCBI 1000 Genomes Browser:

rs730881917

Molecular consequence:

NM_001322011.2:c.-379G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322012.2:c.-379G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000535.7:c.506G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322003.2:c.101G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322004.2:c.101G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322005.2:c.101G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.506G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322007.2:c.188G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322008.2:c.188G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322009.2:c.101G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322010.2:c.101G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322013.2:c.101G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.506G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322015.2:c.197G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.593G>A - 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

methylmalonyl-CoA mutase [Mycolicibacterium monacense DSM 44395]
methylmalonyl-CoA mutase [Mycolicibacterium monacense DSM 44395]
gi|1802095170|gnl|PRJNA521103|EWR22 5|gb|QHP86820.1|

Protein
CR422210 XGC-tailbud Xenopus tropicalis cDNA clone TTbA019b02 5', mRNA sequence
CR422210 XGC-tailbud Xenopus tropicalis cDNA clone TTbA019b02 5', mRNA sequence
gi|48915619|gnl|dbEST|23786212|emb| 210.1|

Nucleotide
JGI_XZT45769.fwd NIH_XGC_tropTad5 Xenopus tropicalis cDNA clone IMAGE:7620765 5'...
JGI_XZT45769.fwd NIH_XGC_tropTad5 Xenopus tropicalis cDNA clone IMAGE:7620765 5', mRNA sequence
gi|74285958|gnl|dbEST|31361484|gb|C 53.2|

Nucleotide

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
SCV000274795	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Sep 15, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29887214, 35451539 Citation Link,
SCV000691079	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 17, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30039884, 31433215, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000274795

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Sep 15, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000691079

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 17, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

Using Somatic Mutations from Tumors to Classify Variants in Mismatch Repair Genes.

Shirts BH, Konnick EQ, Upham S, Walsh T, Ranola JMO, Jacobson AL, King MC, Pearlman R, Hampel H, Pritchard CC.

Am J Hum Genet. 2018 Jul 5;103(1):19-29. doi: 10.1016/j.ajhg.2018.05.001. Epub 2018 Jun 7.

PubMed [citation]

PMID:: 29887214
PMCID:: PMC6035155

Predictive functional assay-based classification of PMS2 variants in Lynch syndrome.

Rayner E, Tiersma Y, Fortuno C, van Hees-Stuivenberg S, Drost M, Thompson B, Spurdle AB, de Wind N.

Hum Mutat. 2022 Sep;43(9):1249-1258. doi: 10.1002/humu.24387. Epub 2022 Apr 28.

PubMed [citation]

PMID:: 35451539
PMCID:: PMC9545740

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000274795.7

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

Description

The p.R169H variant (also known as c.506G>A), located in coding exon 5 of the PMS2 gene, results from a G to A substitution at nucleotide position 506. The arginine at codon 169 is replaced by histidine, an amino acid with highly similar properties. Using a Bayesian analysis that incorporates tumor mutation data, this variant was classified as a variant of uncertain significance (Shirts BH et al. Am J Hum Genet. 2018 Jul 5;103(1):19-29). In an in vitro complementation assay, this variant had reduced mismatch repair activity compared to wild type PMS2 (Rayner E et al. Hum Mutat, 2022 Sep;43:1249-1258). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. 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

From Color Diagnostics, LLC DBA Color Health, SCV000691079.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces arginine with histidine at codon 169 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome (PMID: 31433215) and an individual affected with breast cancer (PMID: 30039884). This variant has been identified in 3/281050 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

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine