rs1555459357

Positions:

• chr16-23621368-A-G
• chr16-23621368-A-T

Variant summary

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

The NM_024675.4(PALB2):​c.3107T>C​(p.Val1036Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,042 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• 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/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.3107T>C	p.Val1036Ala	missense_variant	10/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.3107T>C	p.Val1036Ala	missense_variant	10/13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455042 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 724432

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

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	Jul 29, 2021	This missense variant replaces valine with alanine at codon 1036 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 been detected in an individual affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010785). This variant has not been identified 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	Ambry Genetics	Aug 01, 2023	The p.V1036A variant (also known as c.3107T>C), located in coding exon 10 of the PALB2 gene, results from a T to C substitution at nucleotide position 3107. The valine at codon 1036 is replaced by alanine, an amino acid with similar properties. This alteration has been identified in multiple individuals diagnosed with breast cancer (Dorling et al. N Engl J Med. 2021 02;384:428-439; Ng PS et al. J Med Genet, 2022 May;59:481-491). This amino acid position is highly 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 16, 2022

Variant summary: PALB2 c.3107T>C (p.Val1036Ala) results in a non-conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251404 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3107T>C has been reported in the literature in individuals affected with breast cancer (example Ng_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2022

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1036 of the PALB2 protein (p.Val1036Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 33811135). ClinVar contains an entry for this variant (Variation ID: 490081). 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 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	Benign	0.31
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.085	T;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.8	.;L
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.97	.;D
Vest4		0.77
MutPred		0.31		.;Loss of sheet (P = 0.0457);
MVP		0.53
MPC		0.33
ClinPred		0.94	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.34

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: rs1555459357; hg19: chr16-23632689;