7-5995450-G-A

Variant names:

• chr7-5995450-G-A
• rs3815383
• NM_000535.7:c.903+84C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000535.7(PMS2):​c.903+84C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0738 in 836,554 control chromosomes in the GnomAD database, including 4,767 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (573 hom., cov: 32)
  • Exomes 𝑓: 0.078 (4194 hom.)
• Consequence: PMS2 NM_000535.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0480
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 7-5995450-G-A is Benign according to our data. Variant chr7-5995450-G-A is described in ClinVar as [Benign]. Clinvar id is 596289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.335 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.903+84C>T		intron_variant	Intron 8 of 14	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.903+84C>T		intron_variant	Intron 8 of 14	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.0565 AC: 8597 AN: 152112 Hom.: 572 Cov.: 32

Gnomad AFR AF: 0.0211

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0623

Gnomad ASJ AF: 0.0628

Gnomad EAS AF: 0.348

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.0942

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0418

Gnomad OTH AF: 0.0531

GnomAD4 exome AF: 0.0777 AC: 53171 AN: 684324 Hom.: 4194 AF XY: 0.0803 AC XY: 29563 AN XY: 368242

African (AFR) AF: 0.0189 AC: 342 AN: 18070

American (AMR) AF: 0.0859 AC: 3520 AN: 40992

Ashkenazi Jewish (ASJ) AF: 0.0654 AC: 1383 AN: 21160

East Asian (EAS) AF: 0.362 AC: 12647 AN: 34974

South Asian (SAS) AF: 0.148 AC: 10219 AN: 69258

European-Finnish (FIN) AF: 0.0934 AC: 4692 AN: 50260

Middle Eastern (MID) AF: 0.0368 AC: 157 AN: 4272

European-Non Finnish (NFE) AF: 0.0430 AC: 17667 AN: 410548

Other (OTH) AF: 0.0731 AC: 2544 AN: 34790

GnomAD4 genome AF: 0.0565 AC: 8601 AN: 152230 Hom.: 573 Cov.: 32 AF XY: 0.0613 AC XY: 4566 AN XY: 74438

African (AFR) AF: 0.0211 AC: 875 AN: 41536

American (AMR) AF: 0.0621 AC: 949 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0628 AC: 218 AN: 3472

East Asian (EAS) AF: 0.348 AC: 1803 AN: 5180

South Asian (SAS) AF: 0.159 AC: 766 AN: 4820

European-Finnish (FIN) AF: 0.0942 AC: 998 AN: 10590

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0418 AC: 2842 AN: 68028

Other (OTH) AF: 0.0591 AC: 125 AN: 2114

Alfa AF: 0.0457 Hom.: 31

Bravo AF: 0.0521

Asia WGS AF: 0.244 AC: 845 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 19, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28874130) -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.1
DANN	Benign	0.80
PhyloP100		-0.048
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs3815383; hg19: chr7-6035081; COSMIC: COSV56220430;