7-6008999-C-T

Variant names:

• chr7-6008999-C-T
• rs587780726
• NM_000535.7:c.21G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_000535.7(PMS2):​c.21G>A​(p.Ser7Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,612,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S7S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PMS2 NM_000535.7 splice_region, synonymous
• Scores: Splicing: ADA: 0.0002020
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.03
• Publications: 4 publications found

Genes affected

PMS2 (HGNC:9122): (PMS1 homolog 2, mismatch repair system component) The protein encoded by this gene is a key component of the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. This protein forms heterodimers with the gene product of the mutL homolog 1 (MLH1) gene to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is activated following recognition of mismatches and insertion/deletion loops by the MutS-alpha and MutS-beta heterodimers, and is necessary for removal of the mismatched DNA. There is a DQHA(X)2E(X)4E motif found at the C-terminus of the protein encoded by this gene that forms part of the active site of the nuclease. Mutations in this gene have been associated with hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome) and Turcot syndrome. [provided by RefSeq, Apr 2016]

PMS2 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Lynch syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• ovarian cancer

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Muir-Torre syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 7-6008999-C-T is Benign according to our data. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-6008999-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 230712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.03 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.21G>A	p.Ser7Ser	splice_region_variant, synonymous_variant	Exon 1 of 15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.21G>A	p.Ser7Ser	splice_region_variant, synonymous_variant	Exon 1 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460322 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726474

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53162

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4894

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111818

Other (OTH) AF: 0.00 AC: 0 AN: 60268

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74380

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Sep 19, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PMS2 c.21G>A (p.Ser7Ser) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250326 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.21G>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 230712). Based on the evidence outlined above, the variant was classified as likely benign. -

Feb 15, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Apr 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Mar 10, 2015

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Lynch syndrome 4 Benign:1

Jan 23, 2025

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.4
DANN	Benign	0.90
PhyloP100		-2.0
PromoterAI		0.096	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.016
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587780726; hg19: chr7-6048630;