rs2286680

Positions:

• chr7-5995876-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000535.7(PMS2):​c.804-243G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 152,128 control chromosomes in the GnomAD database, including 2,139 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Genomes: 𝑓 0.16 (2139 hom., cov: 32)
• Consequence: PMS2 NM_000535.7 intron
• Clinical Significance: Benign reviewed by expert panel B:1
• Conservation: PhyloP100: 0.292

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 7-5995876-C-T is Benign according to our data. Variant chr7-5995876-C-T is described in ClinVar as [Benign]. Clinvar id is 91371.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5995876-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.804-243G>A		intron_variant		ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.804-243G>A		intron_variant		1	NM_000535.7	P3

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24116 AN: 152010 Hom.: 2133 Cov.: 32

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.0669

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.153

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.159 AC: 24123 AN: 152128 Hom.: 2139 Cov.: 32 AF XY: 0.160 AC XY: 11882 AN XY: 74368

Gnomad4 AFR AF: 0.215

Gnomad4 AMR AF: 0.105

Gnomad4 ASJ AF: 0.207

Gnomad4 EAS AF: 0.0661

Gnomad4 SAS AF: 0.147

Gnomad4 FIN AF: 0.175

Gnomad4 NFE AF: 0.139

Gnomad4 OTH AF: 0.151

Alfa AF: 0.140 Hom.: 3094

Bravo AF: 0.155

Asia WGS AF: 0.113 AC: 394 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Benign:1

Benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

MAF >1% -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.1
DANN	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs2286680; hg19: chr7-6035507;