5-113043560-A-G

Variant names:

• chr5-113043560-A-G
• NM_001085377.2:c.2726T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001085377.2(MCC):​c.2726T>C​(p.Leu909Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MCC NM_001085377.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.30
• Publications: 0 publications found

Genes affected

MCC (HGNC:6935): (MCC regulator of WNT signaling pathway) This gene is a candidate colorectal tumor suppressor gene that is thought to negatively regulate cell cycle progression. The orthologous gene in the mouse expresses a phosphoprotein associated with the plasma membrane and membrane organelles, and overexpression of the mouse protein inhibits entry into S phase. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.751

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCC	NM_001085377.2	c.2726T>C	p.Leu909Pro	missense_variant	Exon 17 of 19	ENST00000408903.7	NP_001078846.2
MCC	NM_002387.3	c.2156T>C	p.Leu719Pro	missense_variant	Exon 15 of 17		NP_002378.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCC	ENST00000408903.7	c.2726T>C	p.Leu909Pro	missense_variant	Exon 17 of 19	2	NM_001085377.2	ENSP00000386227.3
MCC	ENST00000302475.9	c.2156T>C	p.Leu719Pro	missense_variant	Exon 15 of 17	1		ENSP00000305617.4
MCC	ENST00000515367.6	c.1967T>C	p.Leu656Pro	missense_variant	Exon 15 of 17	5		ENSP00000421615.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 27, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2726T>C (p.L909P) alteration is located in exon 17 (coding exon 17) of the MCC gene. This alteration results from a T to C substitution at nucleotide position 2726, causing the leucine (L) at amino acid position 909 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	N;.;.
PhyloP100		6.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.5	D;D;N
REVEL	Uncertain	0.36
Sift	Benign	0.041	D;D;D
Sift4G	Uncertain	0.035	D;T;D
Polyphen		0.98	D;.;D
Vest4		0.87
MutPred		0.52		Loss of helix (P = 3e-04);.;.;
MVP		0.63
MPC		0.42
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.80
gMVP		0.70
Mutation Taster		=35/65	disease causing

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

Other links and lift over

hg19: chr5-112379257;