NM_000535.7(PMS2):c.101G>T (p.Ser34Ile) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 14, 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:: RCV000485924.9

Allele description [Variation Report for NM_000535.7(PMS2):c.101G>T (p.Ser34Ile)]

NM_000535.7(PMS2):c.101G>T (p.Ser34Ile)

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.101G>T (p.Ser34Ile)

HGVS:

NC_000007.14:g.6005954C>A
NG_008466.1:g.8153G>T
NG_050738.1:g.1704C>A
NM_000535.7:c.101G>TMANE SELECT
NM_001322003.2:c.-305G>T
NM_001322004.2:c.-242-1896G>T
NM_001322005.2:c.-305G>T
NM_001322006.2:c.101G>T
NM_001322007.2:c.-115G>T
NM_001322008.2:c.-52-1896G>T
NM_001322009.2:c.-305G>T
NM_001322010.2:c.-242-1896G>T
NM_001322011.2:c.-784G>T
NM_001322012.2:c.-784G>T
NM_001322013.2:c.-305G>T
NM_001322014.2:c.101G>T
NM_001322015.2:c.-384G>T
NP_000526.2:p.Ser34Ile
NP_001308935.1:p.Ser34Ile
NP_001308943.1:p.Ser34Ile
LRG_161t1:c.101G>T
LRG_161:g.8153G>T
NC_000007.13:g.6045585C>A
NM_000535.5:c.101G>T
NM_000535.6:c.101G>T
NR_136154.1:n.188G>T
p.S34I

Protein change:

S34I

Links:

dbSNP: rs370612538

NCBI 1000 Genomes Browser:

rs370612538

Molecular consequence:

NM_001322003.2:c.-305G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322005.2:c.-305G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322007.2:c.-115G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322009.2:c.-305G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322011.2:c.-784G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322012.2:c.-784G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322013.2:c.-305G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322015.2:c.-384G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001322004.2:c.-242-1896G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001322008.2:c.-52-1896G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001322010.2:c.-242-1896G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000535.7:c.101G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.101G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.101G>T - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.188G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000565380	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Feb 14, 2024)	germline	clinical testing	Citation Link,
SCV001469597	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (May 18, 2023)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 26689913, 32255556, 33471991, 32571878, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000565380

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Feb 14, 2024)

germline

clinical testing

Citation Link,

SCV001469597

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(May 18, 2023)

unknown

clinical testing

PubMed (5)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Patterns and functional implications of rare germline variants across 12 cancer types.

Lu C, Xie M, Wendl MC, Wang J, McLellan MD, Leiserson MD, Huang KL, Wyczalkowski MA, Jayasinghe R, Banerjee T, Ning J, Tripathi P, Zhang Q, Niu B, Ye K, Schmidt HK, Fulton RS, McMichael JF, Batra P, Kandoth C, Bharadwaj M, Koboldt DC, et al.

Nat Commun. 2015 Dec 22;6:10086. doi: 10.1038/ncomms10086.

PubMed [citation]

PMID:: 26689913
PMCID:: PMC4703835

Burden of hereditary cancer susceptibility in unselected patients with pancreatic ductal adenocarcinoma referred for germline screening.

Cremin C, Lee MK, Hong Q, Hoeschen C, Mackenzie A, Dixon K, McCullum M, Nuk J, Kalloger S, Karasinska J, Scudamore C, Kim PTW, Donnellan F, Lam ECS, Lim HJ, Neben CL, Stedden W, Zhou AY, Schaeffer DF, Sun S, Renouf DJ, Schrader KA.

Cancer Med. 2020 Jun;9(11):4004-4013. doi: 10.1002/cam4.2973. Epub 2020 Apr 7.

PubMed [citation]

PMID:: 32255556
PMCID:: PMC7286471

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000565380.9

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

Description

Observed in individuals with personal and/or family history of breast, colorectal, pancreatic and other cancers (PMID: 26689913, 32255556, 33471991, 34326862); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32255556, 26689913, 32571878, 33471991, 11574484, 34326862)

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001469597.3

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

Description

In the published literature, this variant has been reported in an individual affected with pancreatic ductal adenocarcinoma (PDAC) (PMID: 32255556 (2020)), and as a somatic variant in a head and neck squamous cell carcinoma tumor sample (PMID: 26689913 (2015)). It has been reported in individuals with breast cancer in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PMS2)). One functional analysis suggested that this variant may retain ATPase and DNA-binding abilities while disrupting the structure of the N-terminal domain, but additional functional studies are needed to ascertain the global effect of this variant on gene and gene product (PMID: 32571878 (2020)). The frequency of this variant in the general population, 0.00008 (10/125392 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

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

Last Updated: Sep 29, 2024

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