rs769605987

Variant names:

• chr7-5997427-A-G
• rs769605987
• NM_000535.7:c.706-4T>C

Your query was ambiguous. Multiple possible variants found:

• chr7-5997427-A-G
• chr7-5997427-A-T

Variant summary

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

The NM_001406866.1(PMS2):​c.892-4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000031 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: PMS2 NM_001406866.1 splice_region, intron
• Scores: Splicing: ADA: 0.00004095
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.187
• Publications: 2 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: ClinGen, Orphanet
• Lynch syndrome 4

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

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 7-5997427-A-G is Benign according to our data. Variant chr7-5997427-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 230113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406866.1. 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.706-4T>C		splice_region intron	N/A	NP_000526.2
	PMS2	NM_001406866.1		c.892-4T>C		splice_region intron	N/A	NP_001393795.1
	PMS2	NM_001322014.2		c.706-4T>C		splice_region intron	N/A	NP_001308943.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	ENST00000265849.12	TSL:1 MANE Select	c.706-4T>C		splice_region intron	N/A	ENSP00000265849.7
	PMS2	ENST00000382321.5	TSL:1	c.706-4T>C		splice_region intron	N/A	ENSP00000371758.4
	PMS2	ENST00000406569.8	TSL:1	n.706-4T>C		splice_region intron	N/A	ENSP00000514464.1

Frequencies

GnomAD3 genomes AF: 0.0000306 AC: 1 AN: 32716 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000801

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000289 AC: 42 AN: 145122 AF XY: 0.000305

Gnomad AFR exome AF: 0.000229

Gnomad AMR exome AF: 0.000267

Gnomad ASJ exome AF: 0.000153

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000794

Gnomad NFE exome AF: 0.000279

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000362 AC: 3 AN: 82824 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 40122

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

African (AFR) AF: 0.00 AC: 0 AN: 2282

American (AMR) AF: 0.00 AC: 0 AN: 1734

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 680

East Asian (EAS) AF: 0.00 AC: 0 AN: 248

South Asian (SAS) AF: 0.00 AC: 0 AN: 2660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 126

European-Non Finnish (NFE) AF: 0.0000433 AC: 3 AN: 69294

Other (OTH) AF: 0.00 AC: 0 AN: 2882

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0186682), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000306 AC: 1 AN: 32716 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 16112

African (AFR) AF: 0.00 AC: 0 AN: 12508

American (AMR) AF: 0.00 AC: 0 AN: 2984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 712

East Asian (EAS) AF: 0.00 AC: 0 AN: 368

South Asian (SAS) AF: 0.00 AC: 0 AN: 958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 68

European-Non Finnish (NFE) AF: 0.0000801 AC: 1 AN: 12478

Other (OTH) AF: 0.00 AC: 0 AN: 412

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Lynch syndrome 4 (1)
-	-	1	Mismatch repair cancer syndrome 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	3.1
DANN	Benign	0.90
PhyloP100		0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000041
dbscSNV1_RF	Benign	0.0
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: rs769605987; hg19: chr7-6037058;