chr16-23623129-C-T

Variant names:

• chr16-23623129-C-T
• rs878855113
• NM_024675.4:c.2836G>A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_024675.4(PALB2):​c.2836G>A​(p.Ala946Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 missense, splice_region
• Scores: Splicing: ADA: 0.01385
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.0410

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]

ENSG00000261723 (HGNC:58305):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24934757).
• BP6: Variant 16-23623129-C-T is Benign according to our data. Variant chr16-23623129-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 421893.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.2836G>A	p.Ala946Thr	missense_variant, splice_region_variant	Exon 9 of 13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.2836G>A	p.Ala946Thr	missense_variant, splice_region_variant	Exon 9 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Aug 02, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted PALB2 c.2836G>A at the cDNA level, p.Ala946Thr (A946T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PALB2 Ala946Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PALB2 Ala946Thr occurs at a position that is not conserved and is located in the region required for interaction with POLH and POLH DNA synthesis stimulation, region of interaction with RAD51, BRCA2 and POLH, and the WD2 repeat (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether PALB2 Ala946Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Familial cancer of breast Uncertain:1

Jul 29, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 421893). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 946 of the PALB2 protein (p.Ala946Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. -

Hereditary cancer-predisposing syndrome Benign:1

Jul 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.037	T;T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.0	.;M
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.093
Sift	Benign	0.12	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.99	.;D
Vest4		0.33
MutPred		0.24		.;Loss of stability (P = 0.1552);
MVP		0.54
MPC		0.066
ClinPred		0.47	T
GERP RS		2.8
Varity_R		0.16
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.014
dbscSNV1_RF	Benign	0.15
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

LitVar

Other links and lift over

dbSNP: rs878855113; hg19: chr16-23634450; COSMIC: COSV99848772; COSMIC: COSV99848772;