rs2228005

Variant names:

• chr7-5997349-G-C
• rs1805319
• NM_000535.7:c.780C>G

Your query was ambiguous. Multiple possible variants found:

• chr7-5997349-G-C
• chr7-5997349-G-T
• chr7-5997349-G-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000535.7(PMS2):​c.780C>G​(p.Ser260Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.813 in 1,588,048 control chromosomes in the GnomAD database, including 527,150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. S260S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.82 (50628 hom., cov: 27)
  • Exomes 𝑓: 0.81 (476522 hom.)
• Consequence: PMS2 NM_000535.7 synonymous
• Clinical Significance: Benign reviewed by expert panel B:24
• Conservation: PhyloP100: -2.26
• Publications: 48 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 7-5997349-G-C is Benign according to our data. Variant chr7-5997349-G-C is described in ClinVar as Benign. ClinVar VariationId is 36693.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=-2.26 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.893 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000535.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	NM_000535.7	MANE Select	c.780C>G	p.Ser260Ser	synonymous	Exon 7 of 15	NP_000526.2
	PMS2	NM_001406866.1		c.966C>G	p.Ser322Ser	synonymous	Exon 8 of 16	NP_001393795.1
	PMS2	NM_001322014.2		c.780C>G	p.Ser260Ser	synonymous	Exon 7 of 15	NP_001308943.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	ENST00000265849.12	TSL:1 MANE Select	c.780C>G	p.Ser260Ser	synonymous	Exon 7 of 15	ENSP00000265849.7
	PMS2	ENST00000382321.5	TSL:1	c.780C>G	p.Ser260Ser	synonymous	Exon 7 of 11	ENSP00000371758.4
	PMS2	ENST00000406569.8	TSL:1	n.780C>G		non_coding_transcript_exon	Exon 7 of 13	ENSP00000514464.1

Frequencies

GnomAD3 genomes AF: 0.817 AC: 123495 AN: 151176 Hom.: 50590 Cov.: 27

Gnomad AFR AF: 0.843

Gnomad AMI AF: 0.899

Gnomad AMR AF: 0.737

Gnomad ASJ AF: 0.849

Gnomad EAS AF: 0.915

Gnomad SAS AF: 0.812

Gnomad FIN AF: 0.794

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.812

Gnomad OTH AF: 0.815

GnomAD2 exomes AF: 0.802 AC: 200814 AN: 250454 AF XY: 0.808

Gnomad AFR exome AF: 0.842

Gnomad AMR exome AF: 0.651

Gnomad ASJ exome AF: 0.838

Gnomad EAS exome AF: 0.921

Gnomad FIN exome AF: 0.793

Gnomad NFE exome AF: 0.817

Gnomad OTH exome AF: 0.804

GnomAD4 exome AF: 0.813 AC: 1168257 AN: 1436754 Hom.: 476522 Cov.: 27 AF XY: 0.815 AC XY: 583562 AN XY: 716378

African (AFR) AF: 0.842 AC: 27808 AN: 33026

American (AMR) AF: 0.662 AC: 29494 AN: 44558

Ashkenazi Jewish (ASJ) AF: 0.835 AC: 21670 AN: 25956

East Asian (EAS) AF: 0.930 AC: 36787 AN: 39558

South Asian (SAS) AF: 0.816 AC: 69845 AN: 85602

European-Finnish (FIN) AF: 0.798 AC: 42594 AN: 53386

Middle Eastern (MID) AF: 0.841 AC: 4825 AN: 5736

European-Non Finnish (NFE) AF: 0.814 AC: 886244 AN: 1089382

Other (OTH) AF: 0.823 AC: 48990 AN: 59550

GnomAD4 genome AF: 0.817 AC: 123582 AN: 151294 Hom.: 50628 Cov.: 27 AF XY: 0.815 AC XY: 60150 AN XY: 73808

African (AFR) AF: 0.843 AC: 34744 AN: 41202

American (AMR) AF: 0.736 AC: 11132 AN: 15122

Ashkenazi Jewish (ASJ) AF: 0.849 AC: 2945 AN: 3470

East Asian (EAS) AF: 0.914 AC: 4711 AN: 5152

South Asian (SAS) AF: 0.812 AC: 3893 AN: 4792

European-Finnish (FIN) AF: 0.794 AC: 8232 AN: 10362

Middle Eastern (MID) AF: 0.861 AC: 253 AN: 294

European-Non Finnish (NFE) AF: 0.812 AC: 55129 AN: 67880

Other (OTH) AF: 0.818 AC: 1727 AN: 2112

Alfa AF: 0.810 Hom.: 12617

Bravo AF: 0.812

Asia WGS AF: 0.835 AC: 2906 AN: 3478

EpiCase AF: 0.815

EpiControl AF: 0.818

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	Lynch syndrome 4 (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	Lynch syndrome (3)
-	-	2	not provided (2)
-	-	1	Endometrial carcinoma (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4 (1)
-	-	1	Mismatch repair cancer syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.0030
DANN	Benign	0.71
PhyloP100		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=99/1	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: rs1805319; hg19: chr7-6036980; COSMIC: COSV56223185; COSMIC: COSV56223185;