2-189867872-A-T

Variant names:

• chr2-189867872-A-T
• NM_000534.5:c.2416A>T
• PMS1 p.Thr806Ser

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000534.5(PMS1):​c.2416A>T​(p.Thr806Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PMS1 NM_000534.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.686
• Publications: 0 publications found

Genes affected

PMS1 (HGNC:9121): (PMS1 homolog 1, mismatch repair system component) This gene encodes a protein belonging to the DNA mismatch repair mutL/hexB family. This protein is thought to be involved in the repair of DNA mismatches, and it can form heterodimers with MLH1, a known DNA mismatch repair protein. Mutations in this gene cause hereditary nonpolyposis colorectal cancer type 3 (HNPCC3) either alone or in combination with mutations in other genes involved in the HNPCC phenotype, which is also known as Lynch syndrome. [provided by RefSeq, Jul 2008]

PMS1 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000300477 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07137951).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000534.5. 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
	PMS1	NM_000534.5	MANE Select	c.2416A>T	p.Thr806Ser	missense	Exon 11 of 13	NP_000525.1	P54277-1
	PMS1	NM_001321045.2		c.2416A>T	p.Thr806Ser	missense	Exon 12 of 14	NP_001307974.1	P54277-1
	PMS1	NM_001321047.2		c.2416A>T	p.Thr806Ser	missense	Exon 11 of 13	NP_001307976.1	P54277-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS1	ENST00000441310.7	TSL:1 MANE Select	c.2416A>T	p.Thr806Ser	missense	Exon 11 of 13	ENSP00000406490.3	P54277-1
	PMS1	ENST00000409593.5	TSL:1	c.1285A>T	p.Thr429Ser	missense	Exon 5 of 7	ENSP00000387169.1	P54277-4
	PMS1	ENST00000424059.1	TSL:1	n.1971+3898A>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	4.4
DANN	Benign	0.86
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	0.74	N
PhyloP100		0.69
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.027
Sift	Benign	0.64	T
Sift4G	Benign	0.37	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.023
gMVP		0.25
Mutation Taster		=97/3	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

hg19: chr2-190732598;