chr7-5973396-CGGTCAGTTCTGAGAAATGACACCCAGGTTGGCGATGTGTCTCATGGTTGGCCTTCCATGGGGACAGTTCCAGGGGTGGTCCATCTCCCCCATGTGGGTGATCAGTTTCTTCATCTCGCTTGTGTTAAGAGCAGTCCCAATCATCACCTGAGTGTGAGACACAATGGTTCAACGTTTTAGTAGTTTTTTGACGTCAGAATGGCAGCTCTTCAGAAGCATTCTTCTCTAAAATAAGGCTGGACAAGATTACAGCTCAAAAACTACCTTCCCTGAAAAACCTTCCCCCAGAGAAGCCTAGGTTCTAGATCTCAGCCCTCCACCCTTCTGTGAAATCAGGCTCCTTGTGGCTCCTTCAAGGTGGCACCGCCTCCACTCCAGACGCCGACCACACCTGTCTCAGCAGCCACCCTGCCCTCTCACCCTGGCAGGTGCAGCAGCCTCCCAGCAGGCCTCCCTGCCCCACTGCGACCCCTCCGAGCCGCTCTCCACTCAGCAGCCAGTGATTACTTTTAAAGGGCTGTCAGGTTATTCATTCCACTTCACAGCTCTCCCCCTCACCTGAATAAAAGCCCCCGTCTGTCCCCTGA-C

Variant names:

• chr7-5973396-CGGTCAGTTCTGAGAAATGACACCCAGGTTGGCGATGTGTCTCATGGTTGGCCTTCCATGGGGACAGTTCCAGGGGTGGTCCATCTCCCCCATGTGGGTGATCAGTTTCTTCATCTCGCTTGTGTTAAGAGCAGTCCCAATCATCACCTGAGTGTGAGACACAATGGTTCAACGTTTTAGTAGTTTTTTGACGTCAGAATGGCAGCTCTTCAGAAGCATTCTTCTCTAAAATAAGGCTGGACAAGATTACAGCTCAAAAACTACCTTCCCTGAAAAACCTTCCCCCAGAGAAGCCTAGGTTCTAGATCTCAGCCCTCCACCCTTCTGTGAAATCAGGCTCCTTGTGGCTCCTTCAAGGTGGCACCGCCTCCACTCCAGACGCCGACCACACCTGTCTCAGCAGCCACCCTGCCCTCTCACCCTGGCAGGTGCAGCAGCCTCCCAGCAGGCCTCCCTGCCCCACTGCGACCCCTCCGAGCCGCTCTCCACTCAGCAGCCAGTGATTACTTTTAAAGGGCTGTCAGGTTATTCATTCCACTTCACAGCTCTCCCCCTCACCTGAATAAAAGCCCCCGTCTGTCCCCTGA-C
• rs2128656484
• NM_000535.7:c.2446-440_*2del

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Strong PP5

The ENST00000382321.5(PMS2):​c.1243-440_*2del variant causes a exon loss, splice acceptor, splice region, intron change involving the alteration of a conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 18)
• Consequence: PMS2 ENST00000382321.5 exon_loss, splice_acceptor, splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.83
• Publications: 0 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: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.103896104 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP5: Variant 7-5973396-CGGTCAGTTCTGAGAAATGACACCCAGGTTGGCGATGTGTCTCATGGTTGGCCTTCCATGGGGACAGTTCCAGGGGTGGTCCATCTCCCCCATGTGGGTGATCAGTTTCTTCATCTCGCTTGTGTTAAGAGCAGTCCCAATCATCACCTGAGTGTGAGACACAATGGTTCAACGTTTTAGTAGTTTTTTGACGTCAGAATGGCAGCTCTTCAGAAGCATTCTTCTCTAAAATAAGGCTGGACAAGATTACAGCTCAAAAACTACCTTCCCTGAAAAACCTTCCCCCAGAGAAGCCTAGGTTCTAGATCTCAGCCCTCCACCCTTCTGTGAAATCAGGCTCCTTGTGGCTCCTTCAAGGTGGCACCGCCTCCACTCCAGACGCCGACCACACCTGTCTCAGCAGCCACCCTGCCCTCTCACCCTGGCAGGTGCAGCAGCCTCCCAGCAGGCCTCCCTGCCCCACTGCGACCCCTCCGAGCCGCTCTCCACTCAGCAGCCAGTGATTACTTTTAAAGGGCTGTCAGGTTATTCATTCCACTTCACAGCTCTCCCCCTCACCTGAATAAAAGCCCCCGTCTGTCCCCTGA-C is Pathogenic according to our data. Variant chr7-5973396-CGGTCAGTTCTGAGAAATGACACCCAGGTTGGCGATGTGTCTCATGGTTGGCCTTCCATGGGGACAGTTCCAGGGGTGGTCCATCTCCCCCATGTGGGTGATCAGTTTCTTCATCTCGCTTGTGTTAAGAGCAGTCCCAATCATCACCTGAGTGTGAGACACAATGGTTCAACGTTTTAGTAGTTTTTTGACGTCAGAATGGCAGCTCTTCAGAAGCATTCTTCTCTAAAATAAGGCTGGACAAGATTACAGCTCAAAAACTACCTTCCCTGAAAAACCTTCCCCCAGAGAAGCCTAGGTTCTAGATCTCAGCCCTCCACCCTTCTGTGAAATCAGGCTCCTTGTGGCTCCTTCAAGGTGGCACCGCCTCCACTCCAGACGCCGACCACACCTGTCTCAGCAGCCACCCTGCCCTCTCACCCTGGCAGGTGCAGCAGCCTCCCAGCAGGCCTCCCTGCCCCACTGCGACCCCTCCGAGCCGCTCTCCACTCAGCAGCCAGTGATTACTTTTAAAGGGCTGTCAGGTTATTCATTCCACTTCACAGCTCTCCCCCTCACCTGAATAAAAGCCCCCGTCTGTCCCCTGA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1050527.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000382321.5. 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.2446-440_*2del	p.Val816fs	frameshift stop_lost splice_region	Exon 15 of 15	NP_000526.2	P54278-1
	PMS2	NM_000535.7	MANE Select	c.2446-440_*2del		splice_acceptor splice_region 3_prime_UTR intron	Exon 15 of 15	NP_000526.2	P54278-1
	PMS2	NM_001406866.1		c.2632-440_*2del	p.Val878fs	frameshift stop_lost splice_region	Exon 16 of 16	NP_001393795.1	A0A8V8TNX6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	ENST00000265849.12	TSL:1 MANE Select	c.2446-440_*2del	p.Val816fs	frameshift stop_lost splice_region	Exon 15 of 15	ENSP00000265849.7	P54278-1
	PMS2	ENST00000265849.12	TSL:1 MANE Select	c.2446-440_*2del		splice_acceptor splice_region 3_prime_UTR intron	Exon 15 of 15	ENSP00000265849.7	P54278-1
	PMS2	ENST00000382321.5	TSL:1	c.1243-440_*2del		exon_loss splice_acceptor splice_region intron	Exon 11 of 11	ENSP00000371758.4	P54278-2

Frequencies

GnomAD3 genomes Cov.: 18

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 18

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2128656484; hg19: chr7-6013027;