chr7-5973382-C-G

Variant names:

• chr7-5973382-C-G
• rs556089649
• NM_000535.7:c.*17G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000535.7(PMS2):​c.*17G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. 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 0.00046 (0 hom., cov: 19)
  • Exomes 𝑓: 0.00055 (95 hom.)
  • Failed GnomAD Quality Control
• Consequence: PMS2 NM_000535.7 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel U:1 B:12
• Conservation: PhyloP100: -0.371
• Publications: 3 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

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 7-5973382-C-G is Benign according to our data. Variant chr7-5973382-C-G is described in ClinVar as Benign. ClinVar VariationId is 91277.Status of the report is reviewed_by_expert_panel, 3 stars.

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.*17G>C		3_prime_UTR	Exon 15 of 15	NP_000526.2	P54278-1
	PMS2	NM_001406866.1		c.*17G>C		3_prime_UTR	Exon 16 of 16	NP_001393795.1	A0A8V8TNX6
	PMS2	NM_001322014.2		c.*17G>C		3_prime_UTR	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.*17G>C		3_prime_UTR	Exon 15 of 15	ENSP00000265849.7	P54278-1
	PMS2	ENST00000406569.8	TSL:1	n.*247G>C		non_coding_transcript_exon	Exon 13 of 13	ENSP00000514464.1	P54278-3
	PMS2	ENST00000406569.8	TSL:1	n.*247G>C		3_prime_UTR	Exon 13 of 13	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes AF: 0.000458 AC: 56 AN: 122252 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.0000308

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000514

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000975

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000702

Gnomad OTH AF: 0.000620

GnomAD2 exomes AF: 0.0000385 AC: 7 AN: 181594 AF XY: 0.0000305

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000201

Gnomad ASJ exome AF: 0.000122

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000127

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000553 AC: 394 AN: 712486 Hom.: 95 Cov.: 9 AF XY: 0.000525 AC XY: 197 AN XY: 375338

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

African (AFR) AF: 0.000107 AC: 2 AN: 18734

American (AMR) AF: 0.000422 AC: 14 AN: 33172

Ashkenazi Jewish (ASJ) AF: 0.000154 AC: 3 AN: 19454

East Asian (EAS) AF: 0.00 AC: 0 AN: 30864

South Asian (SAS) AF: 0.0000961 AC: 6 AN: 62424

European-Finnish (FIN) AF: 0.000283 AC: 13 AN: 45932

Middle Eastern (MID) AF: 0.000337 AC: 1 AN: 2970

European-Non Finnish (NFE) AF: 0.000721 AC: 335 AN: 464640

Other (OTH) AF: 0.000583 AC: 20 AN: 34296

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.000458 AC: 56 AN: 122320 Hom.: 0 Cov.: 19 AF XY: 0.000408 AC XY: 24 AN XY: 58782

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

African (AFR) AF: 0.0000308 AC: 1 AN: 32514

American (AMR) AF: 0.000514 AC: 6 AN: 11668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3002

East Asian (EAS) AF: 0.00 AC: 0 AN: 3846

South Asian (SAS) AF: 0.00 AC: 0 AN: 3470

European-Finnish (FIN) AF: 0.000975 AC: 8 AN: 8208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 252

European-Non Finnish (NFE) AF: 0.000703 AC: 40 AN: 56936

Other (OTH) AF: 0.000613 AC: 1 AN: 1632

⚠️ 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: 0.00218 Hom.: 11

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Lynch syndrome (3)
-	1	2	Lynch syndrome 4 (3)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.3
DANN	Benign	0.59
PhyloP100		-0.37
Mutation Taster		=100/0	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: rs556089649; hg19: chr7-6013013;