7-124853032-C-T

Position:

• chr7-124853032-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_015450.3(POT1):​c.809G>A​(p.Ser270Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: POT1 NM_015450.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1 O:1
• Conservation: PhyloP100: 5.19

Genes affected

POT1 (HGNC:17284): (protection of telomeres 1) This gene is a member of the telombin family and encodes a nuclear protein involved in telomere maintenance. Specifically, this protein functions as a member of a multi-protein complex that binds to the TTAGGG repeats of telomeres, regulating telomere length and protecting chromosome ends from illegitimate recombination, catastrophic chromosome instability, and abnormal chromosome segregation. Increased transcriptional expression of this gene is associated with stomach carcinogenesis and its progression. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2008]

POT1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-124853032-C-T is Pathogenic according to our data. Variant chr7-124853032-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 139525.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POT1	NM_015450.3	c.809G>A	p.Ser270Asn	missense_variant	10/19	ENST00000357628.8	NP_056265.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POT1	ENST00000357628.8	c.809G>A	p.Ser270Asn	missense_variant	10/19	2	NM_015450.3	ENSP00000350249.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tumor predisposition syndrome 3 Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	Founder variant in Romagna region of Italy -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 13, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects POT1 function (PMID: 24686846, 27869160). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POT1 protein function. ClinVar contains an entry for this variant (Variation ID: 139525). This missense change has been observed in individual(s) with melanoma (PMID: 24686846). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 270 of the POT1 protein (p.Ser270Asn). -

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Oct 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 19, 2024	The p.S270N variant (also known as c.809G>A), located in coding exon 6 of the POT1 gene, results from a G to A substitution at nucleotide position 809. The serine at codon 270 is replaced by asparagine, an amino acid with highly similar properties. This variant was identified in 1/167 Italian individuals with cutaneous melanoma who were CDKN2A/ARF- and CDK4-negative (Pastorino L et al. Cancers (Basel), 2020 04;12:). This variant was also identified in five unrelated melanoma-prone families from Romagna, Italy and described as a founder mutation (Shi J et al. Nat Genet, 2014 May;46:482-6). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D;D
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.3	N;N
REVEL	Pathogenic	0.69
Sift	Benign	0.044	D;D
Sift4G	Benign	0.069	T;T
Polyphen		0.38	B;.
Vest4		0.74
MutPred		0.51		Gain of relative solvent accessibility (P = 0.0479);.;
MVP		0.56
MPC		0.99
ClinPred		0.78	D
GERP RS		6.1
Varity_R		0.38
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587777477; hg19: chr7-124493086; COSMIC: COSV104665380;