chr16-23636149-T-C

Position:

• chr16-23636149-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024675.4(PALB2):​c.397A>G​(p.Ser133Gly) variant causes a missense 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. 15/21 in silico tools predict a benign outcome for this variant. 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: -1.29

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050673574).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.397A>G	p.Ser133Gly	missense_variant	4/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.397A>G	p.Ser133Gly	missense_variant	4/13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250812 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135542

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 17, 2023	This missense variant replaces serine with glycine at codon 133 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 PALB2-related disorders in the literature. This variant has been identified in 1/250812 chromosomes 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	Aug 31, 2018	This sequence variant is a single nucleotide substitution (A>G) that results in a serine to glycine amino acid change at residue 133 in the PALB2 protein. This is a previously reported, rare variant present at a frequency of 0.004% in the gnomAD population database (1/245640 alleles). This variant has not, to our knowledge, been reported in the literature in any context. This amino acid residue lies in a region involved in interaction with RAD51 protein, oligomerization, and focal concentration at DNA damage sites (Uniprot); however, there are benign missense variants located in this region, and multiple computational tools queried predict that this amino acid change will have a neutral effect on protein function. These predictions and the effects of this variant on protein function have not been assessed experimentally, to our knowledge. This site is poorly conserved among vertebrates. Based upon the available evidence, we cannot at this time make a clear assessment if this variant is benign or pathogenic; it is a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 27, 2024	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. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2014	This variant is denoted PALB2 c.397A>G at the cDNA level, p.Ser133Gly (S133G) at the protein level, and results in the change of a Serine to a Glycine (AGT>GGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PALB2 Ser133Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Serine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PALB2 Ser133Gly occurs at a position that is poorly conserved across species and is located in the DNA-binding region and region of interaction with BRCA1 and RAD51 (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether PALB2 Ser133Gly is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 20, 2017	Variant summary: The PALB2 c.397A>G (p.Ser133Gly) variant involves the alteration of a non-conserved nucleotide and 4/5 in silico tools predict a benign outcome for this variant. However, these predictions have yet to be functionally assessed. This variant was found in 1/121372 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic PALB2 variant (0.0001563). In addition, multiple clinical diagnostic laboratories classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 18, 2023

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 133 of the PALB2 protein (p.Ser133Gly). This variant is present in population databases (rs730881881, 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: 182759). 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 tolerated. 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	0.068
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.1
DANN	Benign	0.97
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.2	L
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.016
Sift	Benign	0.10	T
Sift4G	Benign	0.15	T
Polyphen		0.010	B
Vest4		0.12
MutPred		0.10		Gain of relative solvent accessibility (P = 0.005);
MVP		0.26
MPC		0.051
ClinPred		0.16	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.052

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs730881881; hg19: chr16-23647470;