rs863224784

Variant names:

• chr16-23614033-A-C
• rs863224784
• NM_024675.4:c.3172T>G

Your query was ambiguous. Multiple possible variants found:

• chr16-23614033-A-C
• chr16-23614033-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024675.4(PALB2):​c.3172T>G​(p.Ser1058Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.07

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.3172T>G	p.Ser1058Ala	missense_variant	Exon 11 of 13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.3172T>G	p.Ser1058Ala	missense_variant	Exon 11 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Uncertain:1

Apr 12, 2022

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. ClinVar contains an entry for this variant (Variation ID: 216751). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1058 of the PALB2 protein (p.Ser1058Ala). -

Hereditary cancer-predisposing syndrome Uncertain:1

Dec 31, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S1058A variant (also known as c.3172T>G), located in coding exon 11 of the PALB2 gene, results from a T to G substitution at nucleotide position 3172. The serine at codon 1058 is replaced by alanine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.0089	T
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.9	.;L
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.11
Sift	Uncertain	0.019	D;D
Sift4G	Benign	0.12	T;T
Polyphen		0.45	.;B
Vest4		0.59
MutPred		0.29		.;Gain of helix (P = 0.0199);
MVP		0.49
MPC		0.054
ClinPred		0.83	D
GERP RS		5.0
Varity_R		0.15
gMVP		0.23

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

LitVar

Other links and lift over

dbSNP: rs863224784; hg19: chr16-23625354;