NM_000535.7(PMS2):c.1361T>C (p.Leu454Pro) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 26, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000574931.9

Allele description [Variation Report for NM_000535.7(PMS2):c.1361T>C (p.Leu454Pro)]

NM_000535.7(PMS2):c.1361T>C (p.Leu454Pro)

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.1361T>C (p.Leu454Pro)

HGVS:

NC_000007.14:g.5987404A>G
NG_008466.1:g.26703T>C
NM_000535.7:c.1361T>CMANE SELECT
NM_001322003.2:c.956T>C
NM_001322004.2:c.956T>C
NM_001322005.2:c.956T>C
NM_001322006.2:c.1205T>C
NM_001322007.2:c.1043T>C
NM_001322008.2:c.1043T>C
NM_001322009.2:c.956T>C
NM_001322010.2:c.800T>C
NM_001322011.2:c.428T>C
NM_001322012.2:c.428T>C
NM_001322013.2:c.788T>C
NM_001322014.2:c.1361T>C
NM_001322015.2:c.1052T>C
NP_000526.2:p.Leu454Pro
NP_001308932.1:p.Leu319Pro
NP_001308933.1:p.Leu319Pro
NP_001308934.1:p.Leu319Pro
NP_001308935.1:p.Leu402Pro
NP_001308936.1:p.Leu348Pro
NP_001308937.1:p.Leu348Pro
NP_001308938.1:p.Leu319Pro
NP_001308939.1:p.Leu267Pro
NP_001308940.1:p.Leu143Pro
NP_001308941.1:p.Leu143Pro
NP_001308942.1:p.Leu263Pro
NP_001308943.1:p.Leu454Pro
NP_001308944.1:p.Leu351Pro
LRG_161t1:c.1361T>C
LRG_161:g.26703T>C
NC_000007.13:g.6027035A>G
NM_000535.5:c.1361T>C
NM_000535.6:c.1361T>C
NR_136154.1:n.1448T>C

Protein change:

L143P

Links:

dbSNP: rs772659239

NCBI 1000 Genomes Browser:

rs772659239

Molecular consequence:

NM_000535.7:c.1361T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322003.2:c.956T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322004.2:c.956T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322005.2:c.956T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.1205T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322007.2:c.1043T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322008.2:c.1043T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322009.2:c.956T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322010.2:c.800T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322011.2:c.428T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322012.2:c.428T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322013.2:c.788T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.1361T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001322015.2:c.1052T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.1448T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000663428	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Likely benign (Apr 23, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001353133	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 26, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000663428

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Likely benign
(Apr 23, 2018)

germline

clinical testing

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

Citation Link,

SCV001353133

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 26, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

In Silico Systems Biology Analysis of Variants of Uncertain Significance in Lynch Syndrome Supports the Prioritization of Functional Molecular Validation.

Borras E, Chang K, Pande M, Cuddy A, Bosch JL, Bannon SA, Mork ME, Rodriguez-Bigas MA, Taggart MW, Lynch PM, You YN, Vilar E.

Cancer Prev Res (Phila). 2017 Oct;10(10):580-587. doi: 10.1158/1940-6207.CAPR-17-0058. Epub 2017 Aug 1.

PubMed [citation]

PMID:: 28765196
PMCID:: PMC5626617

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Ambry Genetics, SCV000663428.4

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

Description

This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV001353133.3

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

Description

This missense variant replaces leucine with proline at codon 454 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has been identified in 4/251488 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: Apr 20, 2024

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