16-23626322-T-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_024675.4(PALB2):c.2662A>T(p.Ile888Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I888T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.808

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11599085).

BP6

Variant 16-23626322-T-A is Benign according to our data. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801. Variant chr16-23626322-T-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 185801.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4 link	c.2662A>T	p.Ile888Leu	missense_variant	Exon 7 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.2662A>T	p.Ile888Leu	missense_variant	Exon 7 of 13	1	NM_024675.4	ENSP00000261584.4		Q86YC2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

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

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Feb 01, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Mar 06, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces isoleucine with leucine at codon 888 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. -

not provided

Uncertain:1

Mar 13, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24485656, 19609323, 20871615) -

Familial cancer of breast

Uncertain:1

Dec 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 888 of the PALB2 protein (p.Ile888Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 185801). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PALB2 protein function with a negative predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.39

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.021

T;T

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.67

T;T

M_CAP

Benign

0.0058

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

.;M

PhyloP100

-0.81

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.043

Sift

Benign

0.13

T;T

Sift4G

Benign

0.42

T;T

Polyphen

0.037

.;B

Vest4

0.33

MutPred

0.29

.;Loss of sheet (P = 0.1158);

MVP

0.40

MPC

0.072

ClinPred

0.33

GERP RS

-1.0

Varity_R

0.26

gMVP

0.49

Mutation Taster

=83/17

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over