7-5973418-C-G

Variant names:

• chr7-5973418-C-G
• rs1802683
• NM_000535.7:c.2570G>C

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.2570G>C​(p.Gly857Ala) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G857V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.31 (2871 hom., cov: 13)
  • Exomes 𝑓: 0.29 (25635 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Benign reviewed by expert panel B:23
• Conservation: PhyloP100: 5.14
• Publications: 36 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: Orphanet, ClinGen
• Lynch syndrome 4

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

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• 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 (MetaRNN=0.0023892224).
• BP6: Variant 7-5973418-C-G is Benign according to our data. Variant chr7-5973418-C-G is described in ClinVar as Benign. ClinVar VariationId is 36691.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.37 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	NM_000535.7	MANE Select	c.2570G>C	p.Gly857Ala	missense	Exon 15 of 15	NP_000526.2	P54278-1
	PMS2	NM_001406866.1		c.2756G>C	p.Gly919Ala	missense	Exon 16 of 16	NP_001393795.1	A0A8V8TNX6
	PMS2	NM_001322014.2		c.2603G>C	p.Gly868Ala	missense	Exon 15 of 15	NP_001308943.1	A0A8V8TQ50

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	ENST00000265849.12	TSL:1 MANE Select	c.2570G>C	p.Gly857Ala	missense	Exon 15 of 15	ENSP00000265849.7	P54278-1
	PMS2	ENST00000382321.5	TSL:1	c.1367G>C	p.Gly456Ala	missense	Exon 11 of 11	ENSP00000371758.4	P54278-2
	PMS2	ENST00000406569.8	TSL:1	n.*211G>C		non_coding_transcript_exon	Exon 13 of 13	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes AF: 0.310 AC: 29695 AN: 95704 Hom.: 2869 Cov.: 13

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.428

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.390

Gnomad SAS AF: 0.356

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.226

Gnomad NFE AF: 0.279

Gnomad OTH AF: 0.325

GnomAD2 exomes AF: 0.286 AC: 57625 AN: 201394 AF XY: 0.285

Gnomad AFR exome AF: 0.366

Gnomad AMR exome AF: 0.296

Gnomad ASJ exome AF: 0.208

Gnomad EAS exome AF: 0.371

Gnomad FIN exome AF: 0.233

Gnomad NFE exome AF: 0.267

Gnomad OTH exome AF: 0.268

GnomAD4 exome AF: 0.287 AC: 250808 AN: 874968 Hom.: 25635 Cov.: 12 AF XY: 0.288 AC XY: 129536 AN XY: 450506

African (AFR) AF: 0.361 AC: 7731 AN: 21420

American (AMR) AF: 0.300 AC: 10653 AN: 35530

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 4377 AN: 20480

East Asian (EAS) AF: 0.338 AC: 10474 AN: 30980

South Asian (SAS) AF: 0.330 AC: 22122 AN: 67108

European-Finnish (FIN) AF: 0.235 AC: 10791 AN: 45902

Middle Eastern (MID) AF: 0.246 AC: 748 AN: 3042

European-Non Finnish (NFE) AF: 0.282 AC: 172458 AN: 611324

Other (OTH) AF: 0.292 AC: 11454 AN: 39182

GnomAD4 genome AF: 0.310 AC: 29718 AN: 95774 Hom.: 2871 Cov.: 13 AF XY: 0.315 AC XY: 14226 AN XY: 45122

African (AFR) AF: 0.365 AC: 9023 AN: 24710

American (AMR) AF: 0.330 AC: 2847 AN: 8630

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 578 AN: 2544

East Asian (EAS) AF: 0.390 AC: 1093 AN: 2806

South Asian (SAS) AF: 0.357 AC: 868 AN: 2432

European-Finnish (FIN) AF: 0.263 AC: 1571 AN: 5970

Middle Eastern (MID) AF: 0.224 AC: 47 AN: 210

European-Non Finnish (NFE) AF: 0.279 AC: 13012 AN: 46602

Other (OTH) AF: 0.329 AC: 404 AN: 1228

Alfa AF: 0.262 Hom.: 741

Bravo AF: 0.295

ExAC AF: 0.274 AC: 31248

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	Lynch syndrome 4 (5)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	Lynch syndrome (3)
-	-	3	not provided (3)
-	-	1	Endometrial carcinoma (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Lynch syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	16
DANN	Benign	0.77
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.58
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.32	N
PhyloP100		5.1
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.29
Sift	Benign	0.31	T
Sift4G	Benign	0.44	T
Polyphen		0.0	B
Vest4		0.070
MPC		1.9
ClinPred		0.0029	T
GERP RS		2.8
Varity_R		0.045
gMVP		0.46
Mutation Taster		=98/2	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: rs1802683; hg19: chr7-6013049; COSMIC: COSV56220850; COSMIC: COSV56220850;