chr16-23626322-T-A

Variant names:

• chr16-23626322-T-A
• rs786202468
• NM_024675.4:c.2662A>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: -0.808
• Publications: 1 publications found

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

ACMG classification

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	c.2662A>T	p.Ile888Leu	missense_variant	Exon 7 of 13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.2662A>T	p.Ile888Leu	missense_variant	Exon 7 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign: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	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.39
DANN	Uncertain	0.98
DEOGEN2	Benign	0.021	T;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	.;M
PhyloP100		-0.81
PrimateAI	Benign	0.46	T
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	T
GERP RS		-1.0
Varity_R		0.26
gMVP		0.49
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs786202468; hg19: chr16-23637643;