rs202194596

Positions:

• chr16-23637951-C-A
• chr16-23637951-C-G
• chr16-23637951-C-T

Variant summary

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

The ENST00000261584.9(PALB2):​c.110G>T​(p.Arg37Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,460,940 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R37S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PALB2 ENST00000261584.9 missense, splice_region
• Scores: Splicing: ADA: 0.09998
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.37

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 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/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.110G>T	p.Arg37Leu	missense_variant, splice_region_variant	3/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.110G>T	p.Arg37Leu	missense_variant, splice_region_variant	3/13	1	NM_024675.4	ENSP00000261584	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460940 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726824

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: 9.00e-7

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

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 16, 2020	The p.R37L variant (also known as c.110G>T), located in coding exon 3 of the PALB2 gene, results from a G to T substitution at nucleotide position 110. The arginine at codon 37 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2022

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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 490065). 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 arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 37 of the PALB2 protein (p.Arg37Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	0.94	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.8	D;.
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.011	D;.
Polyphen		1.0	D;.
Vest4		0.73
MutPred		0.36		Gain of stability (P = 0.1023);.;
MVP		0.82
MPC		0.36
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.71
gMVP		0.076

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.10
dbscSNV1_RF	Benign	0.31
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: rs202194596; hg19: chr16-23649272;