rs1555458809

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_024675.4(PALB2):​c.3201G>A​(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 0.00000274 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PALB2
NM_024675.4 missense, splice_region

Scores

1
2
16
Splicing: ADA: 0.9682
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3

Conservation

PhyloP100: 1.20
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius 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/exons MANE Protein UniProt
PALB2NM_024675.4 linkuse as main transcriptc.3201G>A p.Met1067Ile missense_variant, splice_region_variant 11/13 ENST00000261584.9 NP_078951.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PALB2ENST00000261584.9 linkuse as main transcriptc.3201G>A p.Met1067Ile missense_variant, splice_region_variant 11/131 NM_024675.4 ENSP00000261584 P1
ENST00000561764.1 linkuse as main transcriptn.186-3596C>T intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1457260
Hom.:
0
Cov.:
30
AF XY:
0.00000276
AC XY:
2
AN XY:
725228
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000361
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000468
Hom.:
0

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Familial cancer of breast Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 24, 2022This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 11 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 484178). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1067 of the PALB2 protein (p.Met1067Ile). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. -
Likely pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJun 24, 2022- -
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 11, 2022The p.M1067I variant (also known as c.3201G>A), located in coding exon 11 of the PALB2 gene, results from a G to A substitution at nucleotide position 3201. The amino acid change results in methionine to isoleucine at codon 1067, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 11, which makes it likely to have some effect on normal mRNA splicing. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. RNA studies have demonstrated that this alteration results in an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, as a missense variant, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthApr 21, 2021This missense variant replaces methionine with isoleucine at codon 1067 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.66
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.43
CADD
Uncertain
25
DANN
Uncertain
0.98
DEOGEN2
Benign
0.029
T;T
Eigen
Benign
0.061
Eigen_PC
Benign
0.11
FATHMM_MKL
Benign
0.75
D
LIST_S2
Benign
0.83
T;T
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.32
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.7
.;L
MutationTaster
Benign
0.95
N
PrimateAI
Benign
0.45
T
PROVEAN
Uncertain
-2.5
D;D
REVEL
Benign
0.082
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
D
GERP RS
5.1
Varity_R
0.39
gMVP
0.24

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.97
dbscSNV1_RF
Pathogenic
0.76
SpliceAI score (max)
0.43
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.43
Position offset: 0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555458809; hg19: chr16-23625325; API