Genetic Variant PALB2:p.Met1067Ile (chr16-23614004-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_024675.4(PALB2):c.3201G>T(p.Met1067Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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 Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1067L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PALB2
NM_024675.4 missense, splice_region

Scores

Splicing: ADA: 0.9690

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.20

Publications

0 publications found

Variant links:

Genes affected

PALB2 (HGNC:26144): (partner and localizer of BRCA2) This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. [provided by RefSeq, Jul 2008]

PALB2 Gene-Disease associations (from GenCC):

hereditary breast carcinoma
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
Fanconi anemia complementation group N
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
pancreatic cancer, susceptibility to, 3
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
familial ovarian cancer
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hereditary nonpolyposis colon cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

PALB2 links:

ENSG00000261723 (HGNC:58305):

ENSG00000261723 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4 link	c.3201G>T	p.Met1067Ile	missense_variant, splice_region_variant	Exon 11 of 13	ENST00000261584.9	NP_078951.2	Q86YC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9 link	c.3201G>T	p.Met1067Ile	missense_variant, splice_region_variant	Exon 11 of 13	1	NM_024675.4	ENSP00000261584.4		Q86YC2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457260

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33382

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26080

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.00

AC:

AN:

86076

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1107992

Other (OTH)

AF:

0.00

AC:

AN:

60228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.029

T;T

Eigen

Benign

0.061

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.32

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

.;L

PhyloP100

1.2

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.5

D;D

REVEL

Benign

0.081

Sift

Benign

0.061

T;D

Sift4G

Benign

0.092

T;T

Polyphen

0.65

.;P

Vest4

0.49

MutPred

0.25

.;Loss of ubiquitination at K1062 (P = 0.0877);

MVP

0.49

MPC

0.12

ClinPred

0.93

GERP RS

5.1

Varity_R

0.39

gMVP

0.24

Mutation Taster

=68/32

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Pathogenic

0.81

SpliceAI score (max)

0.36

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.36

Position offset: 0

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

Publications

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chr16-23614004-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over