NM_000535.7(PMS2):c.2174+6T>C AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jun 12, 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:: RCV000589942.22

Allele description [Variation Report for NM_000535.7(PMS2):c.2174+6T>C]

NM_000535.7(PMS2):c.2174+6T>C

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.2174+6T>C

Other names:

IVS12+6T>C

HGVS:

NC_000007.14:g.5982818A>G
NG_008466.1:g.31289T>C
NM_000535.7:c.2174+6T>CMANE SELECT
NM_001322003.2:c.1769+6T>C
NM_001322004.2:c.1769+6T>C
NM_001322005.2:c.1769+6T>C
NM_001322006.2:c.2018+6T>C
NM_001322007.2:c.1856+6T>C
NM_001322008.2:c.1856+6T>C
NM_001322009.2:c.1769+6T>C
NM_001322010.2:c.1613+6T>C
NM_001322011.2:c.1241+6T>C
NM_001322012.2:c.1241+6T>C
NM_001322013.2:c.1601+6T>C
NM_001322014.2:c.2174+6T>C
NM_001322015.2:c.1865+6T>C
LRG_161t1:c.2174+6T>C
LRG_161:g.31289T>C
NC_000007.13:g.6022449A>G
NM_000535.5:c.2174+6T>C
NM_000535.6:c.2174+6T>C

Links:

dbSNP: rs587780050

NCBI 1000 Genomes Browser:

rs587780050

Molecular consequence:

NM_000535.7:c.2174+6T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001322003.2:c.1769+6T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001322004.2:c.1769+6T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001322005.2:c.1769+6T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001322006.2:c.2018+6T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001322007.2:c.1856+6T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001322008.2:c.1856+6T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001322009.2:c.1769+6T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001322010.2:c.1613+6T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001322011.2:c.1241+6T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001322012.2:c.1241+6T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001322013.2:c.1601+6T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001322014.2:c.2174+6T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001322015.2:c.1865+6T>C - intron variant - [Sequence Ontology: SO:0001627]

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
SCV000149587	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Oct 26, 2022)	germline	clinical testing	Citation Link,
SCV000697334	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Feb 1, 2017)	germline	clinical testing	LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000889624	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Jun 12, 2023)	unknown	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

SCV000149587

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Oct 26, 2022)

germline

clinical testing

Citation Link,

SCV000697334

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Feb 1, 2017)

germline

clinical testing

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000889624

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Jun 12, 2023)

unknown

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
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

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

Details of each submission

From GeneDx, SCV000149587.16

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

Description

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697334.1

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

Description

Variant summary: The PMS2 c.2174+6T>C variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict weakening effect on canonical splicing donor site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 5/94552 control chromosomes at a frequency of 0.0000529, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000889624.4

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

Description

This variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000079 (10/126644 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper PMS2 mRNA splicing . 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: Apr 20, 2024

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