NM_000535.7(PMS2):c.2035A>G (p.Ile679Val) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 13, 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:: RCV000212866.7

Allele description [Variation Report for NM_000535.7(PMS2):c.2035A>G (p.Ile679Val)]

NM_000535.7(PMS2):c.2035A>G (p.Ile679Val)

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.2035A>G (p.Ile679Val)

HGVS:

NC_000007.14:g.5982963T>C
NG_008466.1:g.31144A>G
NM_000535.6:c.2035A>G
NM_000535.7:c.2035A>GMANE SELECT
NM_001322003.2:c.1630A>G
NM_001322004.2:c.1630A>G
NM_001322005.2:c.1630A>G
NM_001322006.2:c.1879A>G
NM_001322007.2:c.1717A>G
NM_001322008.2:c.1717A>G
NM_001322009.2:c.1630A>G
NM_001322010.2:c.1474A>G
NM_001322011.2:c.1102A>G
NM_001322012.2:c.1102A>G
NM_001322013.2:c.1462A>G
NM_001322014.2:c.2035A>G
NM_001322015.2:c.1726A>G
NP_000526.2:p.Ile679Val
NP_001308932.1:p.Ile544Val
NP_001308933.1:p.Ile544Val
NP_001308934.1:p.Ile544Val
NP_001308935.1:p.Ile627Val
NP_001308936.1:p.Ile573Val
NP_001308937.1:p.Ile573Val
NP_001308938.1:p.Ile544Val
NP_001308939.1:p.Ile492Val
NP_001308940.1:p.Ile368Val
NP_001308941.1:p.Ile368Val
NP_001308942.1:p.Ile488Val
NP_001308943.1:p.Ile679Val
NP_001308944.1:p.Ile576Val
LRG_161t1:c.2035A>G
LRG_161:g.31144A>G
NC_000007.13:g.6022594T>C
NM_000535.5:c.2035A>G
NM_000535.7:c.2035A>G
NR_136154.1:n.2122A>G
p.I679V

Protein change:

I368V

Links:

dbSNP: rs587780047

NCBI 1000 Genomes Browser:

rs587780047

Molecular consequence:

NM_000535.7:c.2035A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322003.2:c.1630A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322004.2:c.1630A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322005.2:c.1630A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.1879A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322007.2:c.1717A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322008.2:c.1717A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322009.2:c.1630A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322010.2:c.1474A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322011.2:c.1102A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322012.2:c.1102A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322013.2:c.1462A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.2035A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322015.2:c.1726A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.2122A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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truncated aldo-keto reductase [Homo sapiens]
truncated aldo-keto reductase [Homo sapiens]
gi|7328952|dbj|BAA92887.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000149580	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jun 6, 2022)	germline	clinical testing	Citation Link,
SCV004218974	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Feb 13, 2023)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33471991, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000149580

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Jun 6, 2022)

germline

clinical testing

Citation Link,

SCV004218974

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Feb 13, 2023)

unknown

clinical testing

PubMed (2)
[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

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

Breast Cancer Association Consortium., Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, Wahlström C, Pooley KA, Parsons MT, Fortuno C, Wang Q, Bolla MK, Dennis J, Keeman R, Alonso MR, Álvarez N, Herraez B, Fernandez V, Núñez-Torres R, Osorio A, Valcich J, Li M, et al.

N Engl J Med. 2021 Feb 4;384(5):428-439. doi: 10.1056/NEJMoa1913948. Epub 2021 Jan 20.

PubMed [citation]

PMID:: 33471991
PMCID:: PMC7611105

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, SCV000149580.14

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

#	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, SCV004218974.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The frequency of this variant in the general population, 0.000005 (1/199042 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. To the best of our knowledge, this variant has not been reported in individuals with PMS2-related conditions in the published literature. However, in a case-control study, while the variant was absent from cohort of individuals with breast cancer, it was detected in unaffected controls (PMID: 33471991 (2021), see also LOVD(http://databases.lovd.nl/shared/genes/PMS2)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. 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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