rs1805325

Variant names:

• chr7-5978618-A-G
• rs1805325
• NM_000535.7:c.2253T>C
• PMS2 p.Phe751Phe

Your query was ambiguous. Multiple possible variants found:

• chr7-5978618-A-G
• chr7-5978618-A-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_000535.7(PMS2):​c.2253T>C​(p.Phe751Phe) variant causes a synonymous change. The variant allele was found at a frequency of 0.000371 in 1,603,588 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). The gene PMS2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00092 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (12 hom.)
• Consequence: PMS2 NM_000535.7 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:21
• Conservation: PhyloP100: 4.78
• Publications: 9 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• 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

Specifications for PMS2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 7-5978618-A-G is Benign according to our data. Variant chr7-5978618-A-G is described in ClinVar as Benign. ClinVar VariationId is 36688.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS2: High Homozygotes in GnomAd4 at 5 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.2253T>C	p.Phe751Phe	synonymous	Exon 13 of 15	NP_000526.2	P54278-1
	PMS2	NM_001406866.1		c.2439T>C	p.Phe813Phe	synonymous	Exon 14 of 16	NP_001393795.1	A0A8V8TNX6
	PMS2	NM_001322014.2		c.2253T>C	p.Phe751Phe	synonymous	Exon 13 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.2253T>C	p.Phe751Phe	synonymous	Exon 13 of 15	ENSP00000265849.7	P54278-1
	PMS2	ENST00000382321.5	TSL:1	c.1050T>C	p.Phe350Phe	synonymous	Exon 9 of 11	ENSP00000371758.4	P54278-2
	PMS2	ENST00000406569.8	TSL:1	n.1679-904T>C		intron	N/A	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes AF: 0.000911 AC: 137 AN: 150382 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000542

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.0258

Gnomad EAS AF: 0.000390

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000288

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000266

Gnomad OTH AF: 0.000483

GnomAD2 exomes AF: 0.000176 AC: 44 AN: 249622 AF XY: 0.000126

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00281

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000800

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000314 AC: 456 AN: 1453104 Hom.: 12 Cov.: 31 AF XY: 0.000302 AC XY: 218 AN XY: 722880

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000211 AC: 7 AN: 33148

American (AMR) AF: 0.0000224 AC: 1 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 296 AN: 25780

East Asian (EAS) AF: 0.000127 AC: 5 AN: 39354

South Asian (SAS) AF: 0.0000699 AC: 6 AN: 85844

European-Finnish (FIN) AF: 0.0000379 AC: 2 AN: 52822

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.0000769 AC: 85 AN: 1105838

Other (OTH) AF: 0.000901 AC: 54 AN: 59928

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000924 AC: 139 AN: 150484 Hom.: 5 Cov.: 32 AF XY: 0.000830 AC XY: 61 AN XY: 73478

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000590 AC: 24 AN: 40704

American (AMR) AF: 0.000132 AC: 2 AN: 15162

Ashkenazi Jewish (ASJ) AF: 0.0258 AC: 89 AN: 3444

East Asian (EAS) AF: 0.000390 AC: 2 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4768

European-Finnish (FIN) AF: 0.000288 AC: 3 AN: 10420

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

European-Non Finnish (NFE) AF: 0.000266 AC: 18 AN: 67568

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00113 Hom.: 2

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	1	2	Lynch syndrome 4 (3)
-	-	3	not provided (3)
-	-	2	Lynch syndrome (2)
-	-	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
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.3
DANN	Benign	0.56
PhyloP100		4.8
Mutation Taster		=95/5	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1805325;

hg19: chr7-6018249;