chr16-23607903-C-T

Position:

• chr16-23607903-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024675.4(PALB2):​c.3311G>A​(p.Gly1104Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• 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]

PALB2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2490268).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.3311G>A	p.Gly1104Asp	missense_variant	12/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.3311G>A	p.Gly1104Asp	missense_variant	12/13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461834 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 26, 2023	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1104 of the PALB2 protein (p.Gly1104Asp). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 460988). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The aspartic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2023

The p.G1104D variant (also known as c.3311G>A), located in coding exon 12 of the PALB2 gene, results from a G to A substitution at nucleotide position 3311. The glycine at codon 1104 is replaced by aspartic acid, 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	0.20
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	T;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;L
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.4	N;D
REVEL	Benign	0.066
Sift	Benign	0.25	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.32	.;B
Vest4		0.47
MutPred		0.45		.;Loss of sheet (P = 0.0357);
MVP		0.38
MPC		0.077
ClinPred		0.50	T
GERP RS		3.9
Varity_R		0.29
gMVP		0.55

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;