NM_000535.7(PMS2):c.2445G>A (p.Ser815=) AND not specified

Germline classification:: Likely benign (1 submission)
Last evaluated:: Nov 3, 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:: RCV001420820.9

Allele description [Variation Report for NM_000535.7(PMS2):c.2445G>A (p.Ser815=)]

NM_000535.7(PMS2):c.2445G>A (p.Ser815=)

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.2445G>A (p.Ser815=)

HGVS:

NC_000007.14:g.5977588C>T
NG_008466.1:g.36519G>A
NM_000535.7:c.2445G>AMANE SELECT
NM_001322003.2:c.2040G>A
NM_001322004.2:c.2040G>A
NM_001322005.2:c.2040G>A
NM_001322006.2:c.2289G>A
NM_001322007.2:c.2127G>A
NM_001322008.2:c.2127G>A
NM_001322009.2:c.2073G>A
NM_001322010.2:c.1884G>A
NM_001322011.2:c.1512G>A
NM_001322012.2:c.1512G>A
NM_001322013.2:c.1872G>A
NM_001322014.2:c.2478G>A
NM_001322015.2:c.2136G>A
NP_000526.2:p.Ser815=
NP_001308932.1:p.Ser680=
NP_001308933.1:p.Ser680=
NP_001308934.1:p.Ser680=
NP_001308935.1:p.Ser763=
NP_001308936.1:p.Ser709=
NP_001308937.1:p.Ser709=
NP_001308938.1:p.Ser691=
NP_001308939.1:p.Ser628=
NP_001308940.1:p.Ser504=
NP_001308941.1:p.Ser504=
NP_001308942.1:p.Ser624=
NP_001308943.1:p.Ser826=
NP_001308944.1:p.Ser712=
LRG_161t1:c.2445G>A
LRG_161:g.36519G>A
NC_000007.13:g.6017219C>T
NM_000535.5:c.2445G>A
NM_000535.6:c.2445G>A
NR_136154.1:n.2489G>A
p.S815S

Links:

dbSNP: rs753199796

NCBI 1000 Genomes Browser:

rs753199796

Molecular consequence:

NR_136154.1:n.2489G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000535.7:c.2445G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001322003.2:c.2040G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001322004.2:c.2040G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001322005.2:c.2040G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001322006.2:c.2289G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001322007.2:c.2127G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001322008.2:c.2127G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001322009.2:c.2073G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001322010.2:c.1884G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001322011.2:c.1512G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001322012.2:c.1512G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001322013.2:c.1872G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001322014.2:c.2478G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001322015.2:c.2136G>A - synonymous variant - [Sequence Ontology: SO:0001819]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001623200	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Nov 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001623200

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Nov 3, 2022)

germline

clinical testing

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

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

Impact of deleterious variants in other genes beyond BRCA1/2 detected in breast/ovarian and pancreatic cancer patients by NGS-based multi-gene panel testing: looking over the hedge.

Bono M, Fanale D, Incorvaia L, Cancelliere D, Fiorino A, Calò V, Dimino A, Filorizzo C, Corsini LR, Brando C, Madonia G, Cucinella A, Scalia R, Barraco N, Guadagni F, Pedone E, Badalamenti G, Russo A, Bazan V.

ESMO Open. 2021 Aug;6(4):100235. doi: 10.1016/j.esmoop.2021.100235. Epub 2021 Aug 7.

PubMed [citation]

PMID:: 34371384
PMCID:: PMC8358413

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001623200.2

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

Description

Variant summary: PMS2 c.2445G>A (p.Ser815Ser) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00011 in 194842 control chromosomes, predominantly at a frequency of 0.00038 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. However, this data should be interpreted with caution as the sequencing technology utilized cannot rule out possible pseudogene interference due to sequence overlap in this region. To our knowledge, c.2445G>A has not been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=6) and benign/likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.

#	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: Nov 3, 2024

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