NM_000535.7(PMS2):c.614A>C (p.Gln205Pro) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Sep 13, 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:: RCV000164809.14

Allele description [Variation Report for NM_000535.7(PMS2):c.614A>C (p.Gln205Pro)]

NM_000535.7(PMS2):c.614A>C (p.Gln205Pro)

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.614A>C (p.Gln205Pro)

HGVS:

NC_000007.14:g.5999199T>G
NG_008466.1:g.14908A>C
NM_000535.7:c.614A>CMANE SELECT
NM_001322003.2:c.209A>C
NM_001322004.2:c.209A>C
NM_001322005.2:c.209A>C
NM_001322006.2:c.614A>C
NM_001322007.2:c.296A>C
NM_001322008.2:c.296A>C
NM_001322009.2:c.209A>C
NM_001322010.2:c.209A>C
NM_001322011.2:c.-320A>C
NM_001322012.2:c.-320A>C
NM_001322013.2:c.133-1776A>C
NM_001322014.2:c.614A>C
NM_001322015.2:c.305A>C
NP_000526.2:p.Gln205Pro
NP_001308932.1:p.Gln70Pro
NP_001308933.1:p.Gln70Pro
NP_001308934.1:p.Gln70Pro
NP_001308935.1:p.Gln205Pro
NP_001308936.1:p.Gln99Pro
NP_001308937.1:p.Gln99Pro
NP_001308938.1:p.Gln70Pro
NP_001308939.1:p.Gln70Pro
NP_001308943.1:p.Gln205Pro
NP_001308944.1:p.Gln102Pro
LRG_161t1:c.614A>C
LRG_161:g.14908A>C
NC_000007.13:g.6038830T>G
NM_000535.5:c.614A>C
NM_000535.6:c.614A>C
NR_136154.1:n.701A>C
p.Q205P

Protein change:

Q102P

Links:

dbSNP: rs587779342

NCBI 1000 Genomes Browser:

rs587779342

Molecular consequence:

NM_001322011.2:c.-320A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322012.2:c.-320A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322013.2:c.133-1776A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000535.7:c.614A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322003.2:c.209A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322004.2:c.209A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322005.2:c.209A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.614A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322007.2:c.296A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322008.2:c.296A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322009.2:c.209A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322010.2:c.209A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.614A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322015.2:c.305A>C - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.701A>C - 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

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Carex banksii isolate spm00007406 maturase K (matK) gene, partial cds; chloroplast
gi|1878290475|gb|MN763839.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000215490	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Jul 1, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11574484, 24027009, 25980754, 26163658 Citation Link,
SCV000691091	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 13, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 285143, 18602922, 24027009, 25980754, 25741868
SCV002530369	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Likely pathogenic (May 1, 2021)	germline	curation	PubMed (6) [See all records that cite these PMIDs] 18602922, 25980754, 26247049, 31447099, 27435373, 24027009 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000215490

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Jul 1, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV000691091

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 13, 2023)

germline

clinical testing

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

SCV002530369

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Likely pathogenic
(May 1, 2021)

germline

curation

PubMed (6)
[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

Structure and function of the N-terminal 40 kDa fragment of human PMS2: a monomeric GHL ATPase.

Guarné A, Junop MS, Yang W.

EMBO J. 2001 Oct 1;20(19):5521-31.

PubMed [citation]

PMID:: 11574484
PMCID:: PMC125661

MutS/MutL crystal structure reveals that the MutS sliding clamp loads MutL onto DNA.

Groothuizen FS, Winkler I, Cristóvão M, Fish A, Winterwerp HH, Reumer A, Marx AD, Hermans N, Nicholls RA, Murshudov GN, Lebbink JH, Friedhoff P, Sixma TK.

Elife. 2015 Jul 11;4:e06744. doi: 10.7554/eLife.06744.

PubMed [citation]

PMID:: 26163658
PMCID:: PMC4521584

See all PubMed Citations (10)

Details of each submission

From Ambry Genetics, SCV000215490.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The p.Q205P variant (also known as c.614A>C), located in coding exon 6 of the PMS2 gene, results from an A to C substitution at nucleotide position 614. The glutamine at codon 205 is replaced by proline, an amino acid with similar properties. This alteration was detected in trans with a mutation in PMS2 (c.1A>G) in an individual diagnosed with colon cancer at 20 years, duodenal cancer at 41 years, and lymphoma (age at diagnosis was not provided). The proband had a family history of brain tumors diagnosed in two siblings in their 30s and immunohistochemistry demonstrated loss of PMS2 protein expression in both tumor and adjacent normal tissue (Senter L et al. Gastroenterology. 2008 Aug;135(2):419-28). This alteration was also identified once in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-13.e20). In an in vitro study, this alteration displayed a decrease (~50%) in relative repair efficiency compared to wild type (100%), but was not classified as repair deficient because it had significantly higher repair levels than a known PMS2 mutation (Drost M et al. Hum. Mutat. 2013 Nov; 34(11):1477-80). Based on an internal structural assessment, this alteration may result in generalized destabilization of the ATPase domain near the MSH2/MSH6 binding interface (Guarné A et al. EMBO J. 2001 Oct;20:5521-31; Groothuizen FS et al. Elife. 2015 Jul;4:e06744). This amino acid position is highly conserved in available vertebrate species. 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, but may represent a reduced penetrance allele.

#	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, SCV000691091.5

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

Description

This missense variant replaces glutamine with proline at codon 205 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). A functional study has shown that this variant causes partial reduction in DNA mismatch repair activity of PMS2 protein (PMID: 24027009). This variant has been reported in over ten individuals affected with Lynch syndrome-associated cancers (PMID: 25980754; Clinvar SCV000285143.7, communication with an external laboratory). This variant has also been observed in compound heterozygous state with PMS2 c.1A>G (p.Met1?) in an individual affected with early-onset colon cancer, duodenal cancer, and lymphoma and a family history consistent with constitutional mismatch repair deficiency syndrome (PMID: 18602922). This variant has been identified in 2/251496 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as a Likely 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

From Sema4, Sema4, SCV002530369.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (6)

#	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: Oct 8, 2024

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