7-5987196-G-C

Variant names:

• chr7-5987196-G-C
• rs141458772
• NM_000535.7:c.1569C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000535.7(PMS2):​c.1569C>G​(p.Ser523Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00355 in 1,614,062 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Synonymous variant affecting the same amino acid position (i.e. S523S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0052 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (57 hom.)
• Consequence: PMS2 NM_000535.7 synonymous
• Clinical Significance: Likely benign reviewed by expert panel B:25
• Conservation: PhyloP100: 0.494
• Publications: 15 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 7-5987196-G-C is Benign according to our data. Variant chr7-5987196-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 91306.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=0.494 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00518 (789/152236) while in subpopulation NFE AF = 0.00404 (275/68030). AF 95% confidence interval is 0.00365. There are 9 homozygotes in GnomAd4. There are 497 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR,AD gene

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.1569C>G	p.Ser523Ser	synonymous	Exon 11 of 15	NP_000526.2	P54278-1
	PMS2	NM_001406866.1		c.1755C>G	p.Ser585Ser	synonymous	Exon 12 of 16	NP_001393795.1	A0A8V8TNX6
	PMS2	NM_001322014.2		c.1569C>G	p.Ser523Ser	synonymous	Exon 11 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.1569C>G	p.Ser523Ser	synonymous	Exon 11 of 15	ENSP00000265849.7	P54278-1
	PMS2	ENST00000382321.5	TSL:1	c.804-4205C>G		intron	N/A	ENSP00000371758.4	P54278-2
	PMS2	ENST00000406569.8	TSL:1	n.1569C>G		non_coding_transcript_exon	Exon 11 of 13	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes AF: 0.00519 AC: 789 AN: 152118 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0449

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00404

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00555 AC: 1395 AN: 251154 AF XY: 0.00537

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00497

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0409

Gnomad NFE exome AF: 0.00365

Gnomad OTH exome AF: 0.00490

GnomAD4 exome AF: 0.00338 AC: 4934 AN: 1461826 Hom.: 57 Cov.: 45 AF XY: 0.00333 AC XY: 2418 AN XY: 727200

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00455 AC: 119 AN: 26136

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.0383 AC: 2045 AN: 53362

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00230 AC: 2557 AN: 1112002

Other (OTH) AF: 0.00313 AC: 189 AN: 60396

GnomAD4 genome AF: 0.00518 AC: 789 AN: 152236 Hom.: 9 Cov.: 32 AF XY: 0.00668 AC XY: 497 AN XY: 74416

African (AFR) AF: 0.000313 AC: 13 AN: 41550

American (AMR) AF: 0.000196 AC: 3 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.0449 AC: 476 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00404 AC: 275 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00475 Hom.: 2

Bravo AF: 0.00174

EpiCase AF: 0.00305

EpiControl AF: 0.00255

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	5	not provided (5)
-	-	4	Lynch syndrome 4 (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Lynch syndrome (1)
-	-	1	Malignant tumor of breast (1)
-	-	1	Ovarian neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.53
PhyloP100		0.49
Mutation Taster		=98/2	polymorphism

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: rs141458772; hg19: chr7-6026827;