16-23637952-G-T

Position:

chr16-23637952-G-T

Variant summary

Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BP1

This summary comes from the ClinGen Evidence Repository: The c.109C>A variant in PALB2 is a missense variant predicted to cause substitution of arginine by serine at amino acid 37 (p.Arg37Ser). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00012 in the African population (PM2_Supporting, BS1, and BA1 are not met). This variant is functional in multiple different protein assays (PMID:31636395); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (BP1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA191059/MONDO:0016419/020

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

PALB2
ENST00000261584.9 missense, splice_region

Scores

Splicing: ADA: 0.9304

Clinical Significance

Uncertain significance reviewed by expert panel U:13B:1

Conservation

PhyloP100: 5.53

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got -1 ACMG points.

BP1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.109C>A	p.Arg37Ser	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 linkuse as main transcript	c.109C>A	p.Arg37Ser	missense_variant, splice_region_variant	3/13	1	NM_024675.4	ENSP00000261584	P1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251456

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1460624

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726718

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:13Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:4Benign:1

Uncertain significance, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Apr 05, 2023	The c.109C>A variant in PALB2 is a missense variant predicted to cause substitution of arginine by serine at amino acid 37 (p.Arg37Ser). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00012 in the African population (PM2_Supporting, BS1, and BA1 are not met). This variant is functional in multiple different protein assays (PMID: 31636395); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (BP1) -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 30, 2023	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 37 of the PALB2 protein (p.Arg37Ser). This variant is present in population databases (rs200048921, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 28194609). ClinVar contains an entry for this variant (Variation ID: 185108). 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. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31636395, 33964450). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 03, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 19, 2016	- -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer (Lerner-Ellis et al., 2017; Hauke et al., 2018); Published functional studies demonstrate no significant impact on HDR activity (Wiltshire et al., 2020; Brnich et al., 2021); This variant is associated with the following publications: (PMID: 33195396, 33964450, 20871615, 19369211, 36139699, 28194609, 29522266, 34522520, 31636395) -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 22, 2023	The p.R37S variant (also known as c.109C>A), located in coding exon 3 of the PALB2 gene, results from a C to A substitution at nucleotide position 109. This variant impacts the first base pair of coding exon 3. The arginine at codon 37 is replaced by serine, an amino acid with dissimilar properties. This alteration was found to be functionally normal in DNA-repair assays (Wiltshire T et al. Genet. Med. 2020 03;22:622-632; Brnich SE et al. J Mol Diagn. 2021 07;23:847-864). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 02, 2024	This missense variant replaces arginine with serine at codon 37 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function. Two functional studies have reported that this variant does not impact BRCA1 function in homology-directed repair assays (PMID: 31636395, 33964450). This variant has been reported in an individual affected with breast cancer (PMID: 28194609) and a suspected hereditary breast and ovarian cancer family (PMID: 29522266). This variant has been identified in 4/251456 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	Mendelics	Jul 02, 2018	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 18, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 17, 2021	Variant summary: PALB2 c.109C>A (p.Arg37Ser) results in a non-conservative amino acid change located in the coiled coil domain (Boonen_2020) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251456 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.109C>A has been reported in the literature in at-least one individual affected with ER positive, HER negative breast cancer (example, Lerner-Ellis_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least two publications report primary experimental evidence evaluating an impact on protein function (example, Wiltshire_2020, Brnich_2021 and reviewed in Boonen_2020). These results showed no damaging effect of this variant on homology directed repair activity (Wiltshire_2019) and an intermediate assay read out on homology directed repair function (Brnich_2021). Seven 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. -

PALB2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 16, 2024

The PALB2 c.109C>A variant is predicted to result in the amino acid substitution p.Arg37Ser. This variant was reported in two patients with breast or ovarian cancer (Lerner-Ellis et al. 2017. PubMed ID: 28194609; Hauke et al. 2018. PubMed ID: 29522266). Functional studies are inconclusive regarding the effect of this variant (Wiltshire et al. 2019. PubMed ID: 31636395; Brnich et al. 2021. PubMed ID: 33964450). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. The variant has conflicting classifications in ClinVar, though most submissions classify the variant as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/185108/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Uncertain

0.085

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

T;T

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.86

D;D

M_CAP

Benign

0.043

MetaRNN

Uncertain

0.65

D;D

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.7

M;.

MutationTaster

Benign

0.94

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.9

D;.

REVEL

Benign

0.20

Sift

Pathogenic

0.0

D;.

Sift4G

Benign

0.15

T;.

Polyphen

1.0

D;.

Vest4

0.77

MVP

0.87

MPC

0.36

ClinPred

0.89

GERP RS

5.7

Varity_R

0.72

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.93

dbscSNV1_RF

Benign

0.70

SpliceAI score (max)

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over