rs1060502798

chr16-23607903-C-Achr16-23607903-C-Gchr16-23607903-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_024675.4(PALB2):c.3311G>T(p.Gly1104Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1104D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.802

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 15 uncertain in NM_024675.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.3311G>T	p.Gly1104Val	missense_variant	12/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.3311G>T	p.Gly1104Val	missense_variant	12/13	1	NM_024675.4	P1
	ENST00000561764.1	n.185+520C>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461834 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727220

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 01, 2024

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1104 of the PALB2 protein (p.Gly1104Val). 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: 410203). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	Uncertain	0.40
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.038	T;T
Eigen	Benign	0.18
Eigen_PC	Benign	0.038
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-4.2	D;D
Sift	Uncertain	0.024	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	.;D
Vest4		0.68
MutPred		0.43		.;Gain of sheet (P = 0.0827);
MVP		0.52
MPC		0.33
ClinPred		0.97	D
GERP RS		3.9
Varity_R		0.50
gMVP		0.42

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: rs1060502798; hg19: chr16-23619224;