ClinVar Genomic variation as it relates to human health

This missense variant replaces proline with serine at codon 281 of the BARD1 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 reported in individuals affected with breast cancer and Lynch syndrome-associated cancer and/or polyps (PMID: 25980754, 26976419, 27978560). This variant has also been identified in 4/247946 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.

The p.P281S variant (also known as c.841C>T), located in coding exon 4 of the BARD1 gene, results from a C to T substitution at nucleotide position 841. The proline at codon 281 is replaced by serine, an amino acid with similar properties. This variant was identified in multiple individuals diagnosed with breast cancer (Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8; Sandoval RL et al. PLoS One, 2021 Feb;16:e0247363; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This alteration has been previously identified in an individual from a North American cohort of individuals with early onset colon cancer (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). This variant was also reported in 1/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is not 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.

Variant summary: BARD1 c.841C>T (p.Pro281Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 247946 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.841C>T has been reported in the literature in individuals affected with breast cancer, colorectal cancer, prostate cancer and Lynch syndrome associated cancer and/or polyps (Yurgelun_2015, Tung_2016, Pearlman_2016, Sandoval_2021, Dorling_2021, Dillon_2022). These reports 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. Ten ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Observed in individuals with a personal or family history including breast, colon, or other cancer and/or polyps, and also observed in unaffected controls (PMID: 25980754, 26976419, 27978560, 33471991, 34250417, 33606809, 35534704, 35264596); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25980754, 26976419, 27720647, 27978560, 29596542, 33606809, 33471991, 35264596, 35534704, 34250417)

The BARD1 c.841C>T (p.Pro281Ser) missense change has a maximum subpopulation frequency of 0.0036% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-215645757-G-A?dataset=gnomad_r2_1). It is absent in a database of women older than 70 years of age who have never had cancer (https://whi.color.com/). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but these predictions have not been confirmed by functional studies. This variant has been reported in individuals with breast cancer, colorectal cancer, and suspected Lynch syndrome (PMID: 26976419, 27978560, 25980754). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.

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].

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 281 of the BARD1 protein (p.Pro281Ser). This variant is present in population databases (rs200059956, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer and colon cancer (PMID: 25980754, 26979419, 27978560, 33606809, 34250417). ClinVar contains an entry for this variant (Variation ID: 127749). 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.