NM_000535.7(PMS2):c.2149G>A (p.Val717Met) AND Lynch syndrome 4

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Apr 5, 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:: RCV000411225.18

Allele description [Variation Report for NM_000535.7(PMS2):c.2149G>A (p.Val717Met)]

NM_000535.7(PMS2):c.2149G>A (p.Val717Met)

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.2149G>A (p.Val717Met)

HGVS:

NC_000007.14:g.5982849C>T
NG_008466.1:g.31258G>A
NM_000535.7:c.2149G>AMANE SELECT
NM_001322003.2:c.1744G>A
NM_001322004.2:c.1744G>A
NM_001322005.2:c.1744G>A
NM_001322006.2:c.1993G>A
NM_001322007.2:c.1831G>A
NM_001322008.2:c.1831G>A
NM_001322009.2:c.1744G>A
NM_001322010.2:c.1588G>A
NM_001322011.2:c.1216G>A
NM_001322012.2:c.1216G>A
NM_001322013.2:c.1576G>A
NM_001322014.2:c.2149G>A
NM_001322015.2:c.1840G>A
NP_000526.2:p.Val717Met
NP_001308932.1:p.Val582Met
NP_001308933.1:p.Val582Met
NP_001308934.1:p.Val582Met
NP_001308935.1:p.Val665Met
NP_001308936.1:p.Val611Met
NP_001308937.1:p.Val611Met
NP_001308938.1:p.Val582Met
NP_001308939.1:p.Val530Met
NP_001308940.1:p.Val406Met
NP_001308941.1:p.Val406Met
NP_001308942.1:p.Val526Met
NP_001308943.1:p.Val717Met
NP_001308944.1:p.Val614Met
LRG_161t1:c.2149G>A
LRG_161:g.31258G>A
NC_000007.13:g.6022480C>T
NM_000535.5:c.2149G>A
NM_000535.6:c.2149G>A
NM_001322014.2:c.2149G>A
NR_136154.1:n.2236G>A
p.V717M

Protein change:

V406M

Links:

dbSNP: rs201671325

NCBI 1000 Genomes Browser:

rs201671325

Molecular consequence:

NM_000535.7:c.2149G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322003.2:c.1744G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322004.2:c.1744G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322005.2:c.1744G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.1993G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322007.2:c.1831G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322008.2:c.1831G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322009.2:c.1744G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322010.2:c.1588G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322011.2:c.1216G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322012.2:c.1216G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322013.2:c.1576G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.2149G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322015.2:c.1840G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.2236G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Lynch syndrome 4 (LYNCH4)
Synonyms:: Colorectal cancer, hereditary nonpolyposis, type 4; Hereditary non-polyposis colorectal cancer, type 4
Identifiers:: MONDO: MONDO:0013699; MedGen: C1838333; Orphanet: 144; OMIM: 614337

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000488729	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Jun 1, 2016)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 26845104, 22703879, 23709753, 25186627, 23837913 Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV001324103	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Sep 17, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22703879, 23837913 Citation Link,
SCV004019875	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely benign (Apr 5, 2023)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000488729

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Dominant Disease Classification criteria (2015))

Uncertain significance
(Jun 1, 2016)

unknown

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Counsyl Autosomal Dominant Disease Classification criteria (2015),

Citation Link,

SCV001324103

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Sep 17, 2018)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV004019875

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Likely benign
(Apr 5, 2023)

unknown

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Improving performance of multigene panels for genomic analysis of cancer predisposition.

Shirts BH, Casadei S, Jacobson AL, Lee MK, Gulsuner S, Bennett RL, Miller M, Hall SA, Hampel H, Hisama FM, Naylor LV, Goetsch C, Leppig K, Tait JF, Scroggins SM, Turner EH, Livingston R, Salipante SJ, King MC, Walsh T, Pritchard CC.

Genet Med. 2016 Oct;18(10):974-81. doi: 10.1038/gim.2015.212. Epub 2016 Feb 4.

PubMed [citation]

PMID:: 26845104

Refining the role of PMS2 in Lynch syndrome: germline mutational analysis improved by comprehensive assessment of variants.

Borràs E, Pineda M, Cadiñanos J, Del Valle J, Brieger A, Hinrichsen I, Cabanillas R, Navarro M, Brunet J, Sanjuan X, Musulen E, van der Klift H, Lázaro C, Plotz G, Blanco I, Capellá G.

J Med Genet. 2013 Aug;50(8):552-63. doi: 10.1136/jmedgenet-2012-101511. Epub 2013 May 24.

PubMed [citation]

PMID:: 23709753

See all PubMed Citations (5)

Details of each submission

From Counsyl, SCV000488729.2

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

#	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

From Illumina Laboratory Services, Illumina, SCV001324103.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown 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

From Myriad Genetics, Inc., SCV004019875.1

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

Description

This variant is considered likely benign. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic.

#	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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