NM_000535.7(PMS2):c.2445G>A (p.Ser815=) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Mar 22, 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:: RCV000163748.16

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)

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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Phenazine biosynthesis-like protein domain containing [Mus musculus]
Phenazine biosynthesis-like protein domain containing [Mus musculus]
gi|18044106|gb|AAH19997.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000214324	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Nov 29, 2021)	germline	clinical testing	Citation Link,
SCV002530308	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Aug 26, 2021)	germline	curation	Citation Link,
SCV004358982	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 22, 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

SCV000214324

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Nov 29, 2021)

germline

clinical testing

Citation Link,

SCV002530308

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Aug 26, 2021)

germline

curation

Citation Link,

SCV004358982

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 22, 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	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

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, SCV000214324.7

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

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Sema4, Sema4, SCV002530308.1

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

#	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, SCV004358982.1

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

Description

This synonymous variant is located at the last nucleotide of exon 14 of the PMS2 gene. To our knowledge, RNA studies have not been reported for this variant. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 25/224802 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: Nov 3, 2024

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